A case of Alemtuzumab-induced neutropenia in multiple sclerosis in association with the expansion of large granular lymphocytes.

BACKGROUND: Alemtuzumab has been demonstrated to reduce the risks of relapse and accumulation of sustained disability in Multiple Sclerosis (MS) patients compared to ß-interferon. It acts against CD52, leading primarily to lymphopenia. Recent data have shown that mild neutropenia is observed in 16% of treated MS-patients whereas severe neutropenia occurred in 0.6%. CASE PRESENTATION: Herein, we present the case of a 34-year-old woman with relapsing-remitting MS, with a history of treatment with glatiramer acetate and natalizumab, who subsequently received Alemtuzumab (12 mg / 24 h × 5 days). 70-days after the last Alemtuzumab administration, the patient displayed neutropenia (500 neutrophils/µL) with virtual absence of B-cells (0.6% of total lymphocytes), low values of CD4-T-cells (6.6%) and predominance of CD8-T-cells (48%) and NK-cells (47%); while large granular lymphocytes (LGL) predominated in the blood-smear examination. Due to prolonged neutropenia (5-days) the patient was placed on low-dose corticosteroids leading to sustained remission. CONCLUSION: This is the first case of a patient with relapsing-remitting MS with neutropenia two months post-Alemtuzumab, with simultaneous presence of LGL cells in the blood and a robust therapeutic response to prednisolone. We recommend testing with a complete blood count every 15 days in the first 3 months after the 1st Alemtuzumab administration and searching for large granular lymphocytes cell expansion on microscopic examination of the peripheral blood if neutropenia develops.

Intermittent Atrioventricular Block following Fingolimod Initiation.

A 47-year-old female patient with multiple sclerosis (MS) developed symptomatic intermittent 2nd degree atrioventricular block (AVB) of five-hour duration, five hours after the first two doses of fingolimod, that resolved completely. Frequency domain analysis of heart rate variability (HRV) revealed increased parasympathetic activity and decreased sympathetic tone, while modified Ewing tests were suggestive of impaired cardiac sympathetic function. We hypothesize that expression of this particular arrhythmia might be related to autonomic nervous system (ANS) dysfunction due to demyelinating lesions in the upper thoracic spinal cord, possibly augmented by the parasympathetic effect of the drug.

Abnormal spatial QRS-T angle, a marker of ventricular repolarisation, predicts serious ventricular arrhythmia in systemic sclerosis.

OBJECTIVES: Cardiac involvement may be under-diagnosed in asymptomatic patients with systemic sclerosis (SSc). Standard electrocardiography-derived spatial QRS-T angle (spQRS-Ta) is an established marker of ventricular repolarisation heterogeneity, and a strong independent predictor of cardiac morbidity and mortality, including sudden death, in the general population. We examined whether spQRS-Ta is abnormal in asymptomatic SSc patients and assessed its predictive value for possibly concurrent, serious ventricular arrhythmia. METHODS: SpQRS-Ta and 24-hour Holter recordings were obtained from 69 SSc patients (aged 51±13 years, 63 women) without clinically evident cardiac involvement and having left ventricular ejection fraction at least 50% by echocardiography. 'Healthy' subjects matched 1:1 with patients for age, gender and body mass index served as controls. RESULTS: SpQRS-Ta was wider in SSc (median value 15.6°, interquartile range 10.6-24.3°) than controls (10.5°, 7.3-13.5°, p=0.0001) and not associated with skin fibrosis extent or specific clinical manifestations and autoantibodies. Twenty-four-hour Holter recordings revealed couplets of ventricular beats in six (Lown class IVa) and non-sustained ventricular tachycardia in five patients (Lown class IVb); spQRS-Ta was wider in those eleven patients with serious ventricular arrhythmia than the remaining patients (24.9°, 14.9-31.3° vs. 14.4°, 9.6-22.3°; p=0.02). A spQRS-Ta>19.3° demonstrated 80% sensitivity and 68% specificity (area under the curve 0.81, p=0.02) to predict the presence of non-sustained ventricular tachycardia in Holter monitoring. CONCLUSIONS: Ventricular repolarisation heterogeneity, as reflected by wider spQRS-Ta, is common in SSc. Increased spQRS-Ta could serve as a simple screening test for further investigation to identify patients at risk or prone to develop life-threatening ventricular arrhythmia.

Gender variation of exercise-induced anti-arrhythmic protection: the Ikaria Study.

BACKGROUND: Regular physical activity (PA) has shown substantial cardiac benefits. We sought to investigate whether habitual PA is associated with changes of the electrical action potential duration, as it is represented by the QT duration on a rest ECG, in a population based sample of middle-aged and elderly individuals of Ikaria island. METHODS: In a cross-sectional survey 1071 inhabitants of Ikaria Island (65 ± 13 years, 47% males) were enrolled. PA was estimated by means of IPAQ classifying the participants into low, moderate and vigorous group. QT duration was measured from a surface electrocardiogram; while using Bazett's formula the heart-rate-corrected QT (QTc) was calculated. RESULTS: Among participants, 85% reported at least moderate PA levels. Women in the 'vigorous' and 'moderate' PA level compared to those in the 'low' PA level had significantly shorter QTc (408 ± 2 ms vs. 411 ± 1 ms vs. 419 ± 2 ms, P = 0.001, respectively). In contrast, no significant difference in QTc according to PA levels was observed in men (P = 0.053). Linear regression analysis revealed that PA level was significantly associated with shorter QTc in women after adjustment for established confounders; while no such association was evident in men. Furthermore, compared to the 'low' PA group, women in the 'vigorous' PA group were 5.5-times less likely to have QTc interval above 450 ms (P = 0.031). CONCLUSION: Increased PA is associated with shorter QTc interval only in middle-aged and elderly women of Ikaria Island irrespectively of participant's habits or medical conditions, illustrating gender differences in the cardioprotective effect of habitual exercise.

Myocardial performance and aortic elasticity are impaired in patients with ankylosing spondylitis.

OBJECTIVE: To measure aortic stiffness and global left ventricular (LV) function in patients with ankylosing spondylitis (AS) and no clinical evidence of heart disease. METHODS: Fifty-seven consecutive patients with AS (54 males, three females, mean age 41.78+/-10.02 years) without clinical evidence of cardiac involvement and 78 healthy subjects (73 males, five females, mean age 39.92+/-9.11 years) underwent complete echocardiographic study. Aortic stiffness was determined non-invasively by aortic distensibility (AoD) and the global LV function was evaluated by the myocardial performance index (the Tei index). RESULTS: AoD in patients with AS [(2.21+/-0.24)x10(-6) cm(2) dyn(-1)] was decreased compared to controls [(2.58+/-0.19) )x10(-6) cm(2) dyn(-1), p<0.01], confirming that aortic stiffness is increased in AS. The LV Tei index was significantly increased in the patient group compared to the control group (0.392+/-0.031 vs. 0.370+/-0.034, p<0.01). The ejection fraction (EF) did not differ between the two groups (p>0.05). In multivariate linear regression analysis, AoD was significantly associated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and LV isovolumic relaxation time (IVRT) whereas the LV Tei index was associated with BASDAI and the LV mass index. CONCLUSIONS: Patients with AS and no clinical evidence of cardiac disease have increased stiffness of the aorta and decreased global myocardial performance and both of these abnormal measurements correlate with disease activity. The abnormal Tei index may reflect an early manifestation of cardiac dysfunction in these patients.

Detection of myocardial inflammation by contrast-enhanced MRI in a patient with Churg-Strauss syndrome.

This case report emphasizes the application of a combined CMR protocol for the diagnosis of acute myocardial inflammation and fibrosis in CSS.

Impaired aortic elastic properties in patients with systemic sarcoidosis.

BACKGROUND: Systemic sarcoidosis (Sar) is a granulomatous disorder involving multiple organs. Widespread vascular involvement and microangiopathy are common in patients with Sar. In addition, subclinical cardiac involvement is increasingly recognized in patients with Sar. However, data on the effect of Sar on the elastic properties of the arteries and myocardial performance are limited. In this study we looked for differences in aortic distensibility (AoD) which is an index of aortic elasticity, and myocardial performance of the ventricles, between patients with Sar and healthy subjects. In addition, we examined potential associations between AoD and clinical, respiratory and echocardiographic findings in patients with Sar. MATERIALS AND METHODS: A total of 83 consecutive patients (26 male/57 female, mean age 51.1 +/- 13.3 years) with Sar, without cardiac symptoms, were included. All patients underwent echocardiographic and respiratory evaluation including lung function tests. Additionally, 83 age- and sex-matched healthy subjects served as controls. AoD was determined non-invasively by ultrasonography. RESULTS: AoD was lower in the Sar compared to the control group (2.29 +/- 0.26 vs. 2.45 +/- 0.20 .10(-) (6) cm2 x dyn(-1), P < 0.01), while left ventricular mass (LVM) was higher in the Sar group (221.3 +/- 50.2 vs. 195.6 +/- 31.3 g, P = 0.007). Furthermore, myocardial performance of both ventricles was impaired in the Sar group. Multivariate linear regression analysis in the total sample population demonstrated a significant and independent inverse relationship between AoD and the presence of Sar (P < 0.001). The same analysis in the Sar patients showed that AoD was associated significantly and independently with the stage of Sar, age, systolic blood pressure, LVM and myocardial performance of both ventricles. No significant relationship was found between AoD and disease duration, pulmonary artery pressure or lung function tests. CONCLUSIONS: Presence and severity of Sar are associated with reduced aortic distensibility, irrespective of the disease duration, pulmonary artery pressure and lung function. In addition, patients with Sar have increased LVM and impaired myocardial performance.

Lung scintigraphy with nonspecific human immunoglobulin G ((99m)Tc-HIG) in the evaluation of pulmonary involvement in connective tissue diseases: correlation with pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT).

PURPOSE: In patients with connective tissue diseases (CTD), the early detection and evaluation of the severity of the pulmonary involvement is mandatory. High-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) are considered to be valuable noninvasive diagnostic modalities. Radiopharmaceuticals have also been used for this purpose. Our aim was the evaluation of technetium-labeled human polyclonal immunoglobulin G (HIG) lung scintigraphy in the early detection and assessment of the severity of the pulmonary involvement in CTD patients. METHODS: Fifty-two nonsmoking CTD patients were studied by PFTs, HRCT, and HIG. According to PFTs, patients were divided in group A (impaired PFTs-abnormal pulmonary function) and group B (normal pulmonary function). Semiquantitative analysis was done on HIG and HRCT and corresponding scores were obtained. RESULTS: Significant difference was found between HIG scores in the two groups (0.6 +/- 0.07 vs 0.51 +/- 0.08, P < 0.001). There was a statistically significant negative correlation between HIG scores and PFTs results and a positive correlation between HIG and HRCT scores. HIG demonstrated similar clinical performance to HRCT. At the best cut-off levels of their score (0.56 and 7, respectively), HIG had a superior sensitivity (77.5 vs 57.5%) with lower specificity (75 vs 91.7%). The combination of the two methods increased the sensitivity of abnormal findings at the expense of specificity. CONCLUSIONS: HIG scintigraphy can be used in the early detection and evaluation of the severity of the pulmonary involvement in CTD, whereas, when used in combination with HRCT, the detection of affected patients can be further improved.

Raynaud's phenomenon is correlated with elevated systolic pulmonary arterial pressure in patients with systemic lupus erythematosus.

In patients with Systemic lupus erythematosus (SLE), Raynaud phenomenon (RP) is frequently present and associated with pulmonary hypertension (PHT). Elevated pulmonary artery systolic pressure (PASP) is an indicator of PHT and can be estimated noninvasively. We attempt to explore the significance of RP in SLE and to correlate it with clinical and serological parameters of the disease. The study population consisted of 34 patients (age, sex and disease duration matched) who fulfilled the revised SLE criteria of the American College of Rheumatology, and were categorized into two groups: Group 1 had patients having SLE and RP (2 males/15 females, mean age 45 +/- 18 years) and group 2 had patients with SLE but without RP (3 males/14 females, mean age 40 +/- 14 years. Detailed cardiac ultrasound was performed including measurement of PASP, while clinical and serological features of both groups were collected and correlated. Significant differences were shown in the presence of arterial hypertension (P < 0.05), arthralgias (P < 0.005), arthritis (P < 0.05), myalgias (P < 0.05), alopecia (P < 0.05) and PASP (P < 0.0001). No difference was observed among the cardiac ultrasound indices and the ejection fraction between the two groups. PASP was significantly correlated with RP, while no correlation was observed regarding the disease duration. In patients with SLE, the presence of RP was associated with elevation in PASP. Further investigation is needed to clarify the significance of this relation.

Spatial QRS-T angle: association with diabetes and left ventricular performance.

The spatial QRS-T angle obtained by vectorcardiography is a combined measurement of the electrical activity of the heart and predicts cardiovascular morbidity and mortality. Disturbances in repolarization and depolarization are common in diabetes. No data, however, exist on the effect of diabetes on QRS-T angle. In this study we examined differences in QRS-T angle between type 2 diabetic and non-diabetic subjects; in addition, the potential relationship between QRS-T angle and left ventricular performance as well as glycaemic control were also examined. A total of 74 subjects with type 2 diabetes and 74 non-diabetic individuals, matched for age and sex with the diabetic subjects were examined. All subjects were free of clinically apparent macrovascular complications. Spatial vectorcardiogaphic descriptors of ventricular depolarization and repolarization were reconstructed from the 12-electrocardiographic leads using a computer-based electrocardiogram. Left ventricular mass and performance were measured using M-mode and Doppler echocardiography. QRS-T angle values were higher (by almost 2-fold) in the diabetic in comparison with the non-diabetic subjects (P < 0.001). After multivariate adjustment, QRS-T angle was independently associated with age (P = 0.01), HbA(1c) (P = 0.003), and low-density lipoprotein cholesterol levels (P = 0.04) in the non-diabetic, and with HbA(1c) (P = 0.03) as well as Tei index (P = 0.003) in the diabetic subjects. The spatial QRS-T angle is high in subjects with type 2 diabetes and is associated with glycaemic control and left ventricular performance. The prognostic importance of the higher spQRS-T angle values in subjects with diabetes remains to be evaluated in prospective studies.

CLimate Impacts on Myocardial infarction deaths in the Athens TErritory: the CLIMATE study.

OBJECTIVE: To evaluate the impact of meteorological variables on daily and monthly deaths caused by acute myocardial infarction (AMI). METHODS: All death certificate data from the Athens territory were analysed for AMI deaths in 2001. Daily atmospheric temperature, pressure and relative humidity data were obtained from the National Meteorological Society for Athens for the same year. RESULTS: The total annual number of deaths caused by AMI was 3126 (1953 men) from a population of 2,664,776 (0.117%). Seasonal variation in deaths was significant, with the average daily AMI deaths in winter being 31.8% higher than in summer (9.89 v 7.35, p < 0.001). Monthly variation was more pronounced for older people (mean daily AMI deaths of people older than 70 years was 3.53 in June and 7.03 in December; p < 0.001) and of only marginal significance for younger people. The best predictor of daily AMI deaths was the average temperature of the previous seven days; the relation between daily AMI deaths and seven-day average temperature (R(2) = 0.109, p < 0.001) was U-shaped. Considering monthly AMI death rates, only mean monthly humidity was independently associated with total deaths from AMI (R(2) = 0.541, p = 0.004). CONCLUSION: Ambient temperature is an important predictor of AMI mortality even in the mild climate of a Mediterranean city like Athens, its effects being predominantly evident in the elderly. Mean monthly humidity is another meteorological factor that appears to affect monthly numbers of AMI deaths. These findings may be useful for healthcare and civil protection planning.

Left atrial systolic reserve in idiopathic vs. ischaemic-dilated cardiomyopathy.

PURPOSE: There are studies indicating more pronounced left atrial (LA) systolic dysfunction at rest in idiopathic (IDDC) than in ischaemic-dilated cardiomyopathy (ISDC). It was hypothesized that the findings would be similar with regards LA systolic reserve. METHODS: Twenty-six patients with IDDC, 28 with ISDC and 25 normal controls underwent low-dose dobutamine stress echocardiography (5-10 microg kg(-1) min(-1) IV). Left atrial volumes were echocardiographically determined at rest and during stress at the mitral valve opening (maximal, Vmax), electrocardiographic P wave (onset of atrial systole, Vp) and mitral valve closure (minimal, Vmin) from the apical 4- and 2-chamber views (biplane area-length method). Left atrial systolic function was assessed with the LA-active emptying volume (ACTEV) = Vp-Vmin and fraction (ACTEF) = ACTEV/Vp. RESULTS: Vmax at rest was similar in IDDC and ISDC and greater than in the controls (54.2 +/- 12 vs. 48.5 +/- 18 vs. 27.1 +/- 6.3 cm(3) m(-2), respectively, P < 0.001) and did not change with stress (53.9 +/- 13.8 vs. 46.9 +/- 16.2 vs. 25.8 +/- 5.9 cm(3) m(-2), P < 0.001). The ACTEV at rest was similar in IDDC and ISDC and greater than in the controls (8.6 +/- 3.5 vs. 9.7 +/- 2.9 vs. 6.1 +/- 2.2 cm(3) m(-2) P < 0.01), whereas during the dobutamine infusion it remained unaltered in IDDC (10.8 +/- 4.6 cm(3) m(-2), P = NS vs. rest) and increased in ISDC (11.8 +/- 3.3 cm(3) m(-2), P < 0.05) and the controls (13.1 +/- 3.2 cm(3) m(-2), P < 0.01). The ACTEF was lower in IDDC than ISDC and the controls at rest (20 +/- 10% vs. 33 +/- 8% vs. 36 +/- 10%, P < 0.01). Dobutamine infusion was associated with no significant increase in ACTEF in IDDC (25 +/- 12%, P = NS vs. rest), and with an increase in this variable in ISDC (39 +/- 10%, P < 0.05) and the controls (49 +/- 12%, P < 0.01). CONCLUSIONS: Dobutamine infusion is associated with an increase in LA ACTEV and fraction in ISDC and no significant change in these indices in IDDC. These findings indicate a reduced LA systolic reserve in IDDC.

Aortic stiffness in systemic sclerosis is increased independently of the extent of skin involvement.

OBJECTIVE: To study the stiffness of large arteries in relation to the extent of skin and lung fibrosis, aortic distensibility was examined in patients with diffuse and limited systemic sclerosis (SSc). METHODS: Consecutive patients (55 with diffuse and 51 with limited SSc) without signs and symptoms of heart failure or a previous history of arterial hypertension underwent echocardiography and lung function tests. Aortic stiffness was determined non-invasively by aortic distensibility and aortic strain measurements in all patients and in 50 healthy subjects, matched for age and gender. RESULTS: Aortic distensibility in patients with either diffuse (2.03 +/- 0.26 x 10(-6) cm(2) dyn(-1)) or limited SSc (2.12 +/- 0.33) was similarly decreased compared with controls (2.49 +/- 0.36, P<0.001). Moreover, aortic strain was significantly reduced in both patient groups compared with controls, confirming that aortic stiffness is increased in SSc independently of the extent of skin involvement. Left ventricular performance was similar between patients and controls, while left ventricular mass and tricuspid systolic gradient were significantly increased in both SSc groups, the latter being associated with aortic stiffness in multivariate analysis. No association with serum levels of C-reactive protein or lung function abnormalities indicative of pulmonary fibrosis were found. CONCLUSIONS: Stiffness of the aorta is increased in patients with established SSc regardless of the extent of the inflammatory fibrotic process in the skin and lungs, suggesting that additional pathogenetic mechanisms contribute to the compromise of large arteries.

Systemic sclerosis is not associated with clinical or ambulatory blood pressure.

BACKGROUND: Raynaud's phenomenon is often the first symptom and occurs eventually in more than 95% of patients with systemic sclerosis (SSc). Angiographic studies disclose narrowing and obstruction of the digital arteries, which on autopsy histologic study show prominent subintimal connective tissue proliferation without inflammation, as well as adventitial fibrosis. It is also known that primary cardiac problems include pericarditis, left ventricular or biventricular failure, serious supraventricular or ventricular arrhythmias emerge in patients with SSc. It is not known if these patients present hypertension or hypotension and which parameter of the ambulatory blood pressure may influence such a disease course. METHODS: A total of 85 subjects underwent clinical blood pressure (BP) readings, 24-hour ambulatory BP monitoring, left ventricular assessment by echocardiography and measurement of intima media thickness (IMT) of the right-left internal carotid arteries (RICA and LICA) and right-left common carotid arteries (RCCA and LCCA). The population consisted of 40 subjects with SSc according to the criteria of the American College of Rheumatology (SCL-group) who were not receiving any antihypertensive treatment and 45 healthy volunteers (control group). The two groups did not differ in age. RESULTS: Clinical systolic and diastolic blood pressure, clinical heart rate, mean 24 h systolic blood pressure, SD systolic blood pressure, mean 24 h diastolic blood pressure, SD 24 h diastolic blood pressure, mean 24 h heart rate, SD 24 h heart rate, pulse pressure 24 h, serum glucose, cholesterol, triglycerides, HDL, LDL, creatinine, urea, potassium and natrium did not statistically significant differ between the two groups. Furthermore, the left ventricular mass/BSA and IMT of both carotid arteries did not show a statistically significant difference between the groups. CONCLUSION: Systemic sclerosis is not associated with clinical blood pressure or the parameter of 24 h blood pressure monitoring.

The effects of cigarette smoking on the heterogeneity of ventricular repolarization.

BACKGROUND: Although the circulatory effects of cigarette smoking have been studied extensively, its impact on ventricular repolarization has not been adequately evaluated. METHODS: The goal of our study was to determine whether cigarette smoking influences the spatial and temporal heterogeneity of ventricular repolarization in a population of young, healthy, male subjects. A digital 12-lead surface electrocardiogram was obtained from 1394 men recruited from the Hellenic Air Force and classified as smokers and nonsmokers. The maximum, minimum, and median QT intervals, QT dispersion (QT maximum - QT minimum), the rate-corrected maximum and median QT intervals, the slopes of the QT maximum/RR and QT median/RR regression equations, and the vectorcardiographic markers spatial T amplitude and spatial QRS-T angle were evaluated in the 2 groups. RESULTS: Heart rate was significantly higher (P <.001) in smokers (n =691) compared with nonsmokers (n = 703). QT maximum, QT minimum, and QT median were significantly lower (P <.001), whereas the rate-corrected QT maximum (P =.04) and QT median (P =.06) were marginally higher in smokers than in nonsmokers. The spatial T amplitude was lower (P =.002), whereas the spatial QRS-T angle was higher (P =.01) in smokers compared with nonsmokers. Neither QT dispersion nor the slopes of the QT/RR and the spatial descriptors/RR regression equations differed between smokers and nonsmokers. CONCLUSIONS: Ventricular repolarization is altered in young male cigarette smokers. The differences in the heterogeneity of ventricular repolarization between smokers and nonsmokers are mainly due to heart rate differences between the 2 study groups.