Characterisation of isocitrate dehydrogenase gene mutant WHO grade 2 and 3 gliomas: MRI predictors of 1p/19q co-deletion and tumour grade.

AIM: To identify imaging predictors of molecular subtype and tumour grade in patients with isocitrate dehydrogenase (IDH) gene mutant (IDHmut) World Health Organization (WHO) grade 2 or 3 gliomas. MATERIALS AND METHODS: Patients with histologically confirmed WHO grade 2 or 3 IDHmut gliomas between 2016 and 2019 were included in the study. Magnetic resonance imaging (MRI) images were evaluated for the presence or absence of potential imaging predictors of tumour subtype, such as T2/fluid attenuated inversion recovery (FLAIR) signal match, and these factors were examined using regression analysis. On perfusion imaging, the maximum relative cerebral blood volume (rCBVmax) was evaluated as a potential predictor of tumour grade. The performance of two experienced neuroradiologists in correctly predicting tumour type on MRI was evaluated. RESULTS: Eighty-five patients were included in the study. The presence of T2/FLAIR signal match >50% of tumour volume (p<0.01) and intratumoural susceptibility (p=0.02) were independent predictors of 1p/19q co-deletion. Mean rCBV max was significantly higher in WHO grade 3 astrocytomas (p=0.04) than WHO grade 2 astrocytomas. The consensus prediction of 1p/19q co-deletion status by two neuroradiologists of tumour was 95% sensitive and 86% specific. CONCLUSION: The presence of matched T2/FLAIR signal could be used to identify tumour subtype when biopsy is inconclusive or genetic analysis is unavailable. rCBVmax predicted astrocytoma grade. Experienced neuroradiologists predict tumour subtype with good sensitivity and specificity.

Coronary microvascular dysfunction correlates with the new onset of cardiac allograft vasculopathy in heart transplant patients with normal coronary angiography.

Coronary microvascular dysfunction is emerging as a strong predictor of outcome in heart transplantation (HT). We assessed the validity of microvascular dysfunction, defined by means of a reduced coronary flow reserve (CFR), as a factor associated with new onset epicardial cardiac allograft vasculopathy (CAV) or death. We studied 105 patients at 4 ± 1 years post-HT with a normal coronary angiography (CA). New onset CAV was assessed by CA. CFR was assessed in the left anterior descending (LAD) coronary artery by transthoracic Doppler echocardiography and calculated as the ratio of hyperaemic to basal blood flow velocity. A CFR ≤ 2.5 was considered abnormal. Epicardial CAV onset or death was assessed during a follow-up of 10 years. New onset CAV was diagnosed in 30 patients (28.6%) (Group A), and the CA was normal in the remaining 75 patients (71.4%) (Group B). Group A had reduced CFR compared with group B (2.4 ± 0.6 vs. 3.2 ± 0.7, p < 0.0001). A CFR ≤ 2.5 was independently associated with a higher probability of new onset CAV (p < 0.0001) and a higher probability of death, regardless of CAV onset (p < 0.01). Microvascular dysfunction is independently associated with the onset of epicardial CAV, and associated with a higher risk of death, regardless of CAV onset.

Functional connectivity changes and their relationship with clinical disability and white matter integrity in patients with relapsing-remitting multiple sclerosis.

BACKGROUND AND OBJECTIVE: To define the pathological substrate underlying disability in multiple sclerosis by evaluating the relationship of resting-state functional connectivity with microstructural brain damage, as assessed by diffusion tensor imaging, and clinical impairments. METHODS: Thirty relapsing-remitting patients and 24 controls underwent 3T-MRI; motor abilities were evaluated by using measures of walking speed, hand dexterity and balance capability, while information processing speed was evaluated by a paced auditory serial addiction task. Independent component analysis and tract-based spatial statistics were applied to RS-fMRI and diffusion tensor imaging data using FSL software. Group differences, after dual regression, and clinical correlations were modelled with General-Linear-Model and corrected for multiple comparisons. RESULTS: Patients showed decreased functional connectivity in 5 of 11 resting-state-networks (cerebellar, executive-control, medial-visual, basal ganglia and sensorimotor), changes in inter-network correlations and widespread white matter microstructural damage. In multiple sclerosis, corpus callosum microstructural damage positively correlated with functional connectivity in cerebellar and auditory networks. Moreover, functional connectivity within the medial-visual network inversely correlated with information processing speed. White matter widespread microstructural damage inversely correlated with both the paced auditory serial addiction task and hand dexterity. CONCLUSIONS: Despite the within-network functional connectivity decrease and the widespread microstructural damage, the inter-network functional connectivity changes suggest a global brain functional rearrangement in multiple sclerosis. The correlation between functional connectivity alterations and callosal damage uncovers a link between functional and structural connectivity. Finally, functional connectivity abnormalities affect information processing speed rather than motor abilities.

Intraplaque hemorrhage in cardiac allograft vasculopathy.

Plaque hemorrhage, inflammation and microvessel density are key determinants of plaque vulnerability in native coronary atherosclerosis (ATS). This study investigates the role of intraplaque hemorrhage (IPH) and its relation with inflammation and microvessels in cardiac allograft vasculopathy (CAV) in posttransplanted patients. Seventy coronary plaques were obtained from 12 patients who died because of CAV. For each patient we collected both native heart and the allograft, at the time of transplantation and autopsy, respectively. Intralesion inflammation, microvessels and IPH were assessed semi-quantitatively. IPH was observed in 21/35 (60%) CAV lesions and in 8/35 (22.9%) native ATS plaques, with a strong association between fibrocellular lesions and IPH (p = 0.0142). Microvessels were detected in 26/35 (74.3%) of CAV lesions with perivascular leakage as sign of endothelial damage in 18/26 (69.2%). IPH was strongly associated with microvessels (p < 0.0001). Inflammation was present in 31/35 (88.6%) of CAV lesions. CAV IPH+ lesions were characterized by presence of both fresh and old hemorrhage in 12/21 (57.1%). IPH, associated with microvessel damage and inflammation, is an important feature of CAV. Fresh and old intralesion hemorrhage suggests ongoing remodeling processes promoting the lesion progression and vulnerability.

Systemic inflammation is related to coronary microvascular dysfunction in obese patients without obstructive coronary disease.

BACKGROUND AND AIMS: Obesity, systemic inflammation and changes in the heart functions are associated with increased cardiovascular risk. This study aimed to investigate coronary microvascular dysfunction as an early marker of atherosclerosis in obese patients without any evidence of cardiovascular disease. METHODS AND RESULTS: 86 obese subjects (aged 44 ± 12 years, body mass index (BMI) 41 ± 8 kg m(-2)), without evidence of heart disease, and 48 lean controls were studied using transthoracic Doppler echocardiography for detecting coronary flow reserve (CFR). A value of CFR ≤ 2.5 was considered abnormal. We measured interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and adiponectin in all patients. Patients with abnormal CFR underwent coronary multislice computed tomography (MSCT) in order to exclude an epicardial stenosis. CFR in obese subjects was lower than in lean subjects (3.2 ± 0.8 vs. 3.7 ± 0.7, p = 0.02) and was abnormal in 27 (31%) obese patients and in one (2%) control (p < 0.0001). All subjects with abnormal CFR showed no coronary stenosis at MSCT. At multivariable analysis, IL-6 and TNF-α were the only determinants of CFR (p < 0.02 and p < 0.02, respectively). At multivariable logistic regression analysis, IL-6 and TNF-α were the only determinants of CFR ≤ 2.5 (p < 0.03 and p < 0.03, respectively). CONCLUSIONS: CFR is often reduced in obese subjects without clinical evidence of heart disease, suggesting a coronary microvascular impairment. This microvascular dysfunction seems to be related to a chronic inflammation mediated by adipocytokines. Our findings may explain the increased cardiovascular risk in obesity, independently of BMI.

COVID-19 Stroke Apical Lung Examination Study 2: a national prospective CTA biomarker study of the lung apices, in patients presenting with suspected acute stroke (COVID SALES 2).

BACKGROUND: Apical ground-glass opacification (GGO) identified on CT angiography (CTA) performed for suspected acute stroke was developed in 2020 as a coronavirus-disease-2019 (COVID-19) diagnostic and prognostic biomarker in a retrospective study during the first wave of COVID-19. OBJECTIVE: To prospectively validate whether GGO on CTA performed for suspected acute stroke is a reliable COVID-19 diagnostic and prognostic biomarker and whether it is reliable for COVID-19 vaccinated patients. METHODS: In this prospective, pragmatic, national, multi-center validation study performed at 13 sites, we captured study data consecutively in patients undergoing CTA for suspected acute stroke from January-March 2021. Demographic and clinical features associated with stroke and COVID-19 were incorporated. The primary outcome was the likelihood of reverse-transcriptase-polymerase-chain-reaction swab-test-confirmed COVID-19 using the GGO biomarker. Secondary outcomes investigated were functional status at discharge and survival analyses at 30 and 90 days. Univariate and multivariable statistical analyses were employed. RESULTS: CTAs from 1,111 patients were analyzed, with apical GGO identified in 8.5 % during a period of high COVID-19 prevalence. GGO showed good inter-rater reliability (Fleiss κ = 0.77); and high COVID-19 specificity (93.7 %, 91.8-95.2) and negative predictive value (NPV; 97.8 %, 96.5-98.6). In subgroup analysis of vaccinated patients, GGO remained a good diagnostic biomarker (specificity 93.1 %, 89.8-95.5; NPV 99.7 %, 98.3-100.0). Patients with COVID-19 were more likely to have higher stroke score (NIHSS (mean +/- SD) 6.9 +/- 6.9, COVID-19 negative, 9.7 +/- 9.0, COVID-19 positive; p = 0.01), carotid occlusions (6.2 % negative, 14.9 % positive; p = 0.02), and larger infarcts on presentation CT (ASPECTS 9.4 +/- 1.5, COVID-19 negative, 8.6 +/- 2.4, COVID-19 positive; p = 0.00). After multivariable logistic regression, GGO (odds ratio 15.7, 6.2-40.1), myalgia (8.9, 2.1-38.2) and higher core body temperature (1.9, 1.1-3.2) were independent COVID-19 predictors. GGO was associated with worse functional outcome on discharge and worse survival after univariate analysis. However, after adjustment for factors including stroke severity, GGO was not independently predictive of functional outcome or mortality. CONCLUSION: Apical GGO on CTA performed for patients with suspected acute stroke is a reliable diagnostic biomarker for COVID-19, which in combination with clinical features may be useful in COVID-19 triage.

Low serum 25-hydroxyvitamin D levels are associated with left ventricular hypertrophy in essential hypertension.

BACKGROUND AND AIM: Low serum 25-hydroxyvitamin D [25(OH)D] levels may have an important role in predisposing to hypertension and myocardial disease. We investigated the relationship between 25(OH)D and left ventricular (LV) structure and function, assessed by echocardiography, in a series of patients with essential hypertension (EH). METHODS AND RESULTS: Sixty-two newly diagnosed never-treated patients (32 male/30 female), aged 18-65 years, with grade 1-2 hypertension, no diabetes, no obesity, no hyperlipidemia, and no cardiopulmonary, renal, or hepatic disease, were studied. Twenty-four healthy normotensive sex-, age-, BMI-matched subjects served as controls. Hypertensive patients with 25(OH)D deficiency, defined as serum 25(OH)D levels <50 nmol/L, had higher prevalence of LV hypertrophy (LVH) than their 25(OH)D-sufficient counterparts (57.1 vs 17.6%, P = 0.02); no differences between the two groups were found in blood pressure levels as well as in other biochemical and hormone parameters. There was an inverse correlation between LV mass index and 25(OH)D levels (r = -0.366, P < 0.003) and a direct correlation between LV mass index and BMI (r = 0.333, P < 0.006) in the entire hypertensive population. The two variables remained independently associated with LVH at multivariable logistic regression analysis (OR 1.05, P < 0.005 and OR 1.25, P = 0.03, respectively). Prevalence of 25(OH)D deficiency was similar in EH patients and controls (45.1 vs 41.6%, P = 0.89), whereas no correlation between echocardiographic parameters and hormone levels was found. CONCLUSIONS: In the absence of major cardiovascular risk factors, 25(OH)D deficiency is a frequent finding in EH patients and is independently associated with LVH.

Coronary flow reserve by transthoracic echocardiography predicts epicardial intimal thickening in cardiac allograft vasculopathy.

Cardiac allograft vasculopathy (CAV) is the leading cause of morbidity and mortality in heart transplantation (HT). We sought to investigate the role of coronary flow reserve (CFR) by contrast-enhanced transthoracic echocardiography (CE-TTE) in CAV diagnosis. CAV was defined as maximal intimal thickness (MIT) assessed by intravascular ultrasound (IVUS) > or =0.5 mm. CFR was assessed in the left anterior descending coronary artery in 22 HT recipients at 6 +/- 4 years post-HT. CAV was diagnosed in 10 patients (group A), 12 had normal coronaries (group B). The mean MIT was 0.7 +/- 0.1 mm (range 0.03-1.8). MIT was higher in group A (1.16 +/- 0.3 mm vs. 0.34 +/- 0.07 mm, p < 0.0001). CFR was 3.1 +/- 0.8 in all patients and lower in group A (2.5 +/- 0.6 vs. 3.7 +/- 0.3, p < 0.0001). CFR was inversely related with MIT (r =-0.774, p < 0.0001). A cut point of < or =2.9, identified as optimal by receiver operating characteristics analysis was 100% specific and 80% sensitive (PPV = 100%, NPV = 89%, Accuracy = 91%). CFR assessment by CE-TTE is a novel noninvasive diagnostic tool in the detection of CAV defined as MIT > or =0.5 mm. CFR by CE-TTE may reduce the need for routine IVUS in HT.

Non-alcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in essential hypertension.

BACKGROUND AND AIM: Insulin resistance is recognized as the pathophysiological hallmark of non-alcoholic fatty liver disease (NAFLD). A relation between insulin sensitivity and left ventricular morphology and function has been reported in essential hypertension, where a high prevalence of NAFLD has been recently found. We investigated the inter-relationship between left ventricular morphology/function, metabolic parameters and NAFLD in 86 never-treated essential hypertensive patients subdivided in two subgroups according to the presence (n = 48) or absence (n = 38) of NAFLD at ultrasonography. METHODS AND RESULTS: The two groups were similar as to sex, age and blood pressure levels. No patient had diabetes mellitus, obesity, hyperlipidemia, or other risk factors for liver disease. Body mass index, waist circumference, triglycerides, glucose, insulin, homeostasis model of assessment index for insulin resistance (HOMA-IR), aspartate aminotransferase and alanine aminotransferase were higher and adiponectin levels were lower in patients with NAFLD than in patients without NAFLD, and were associated with NAFLD at univariate analysis. Patients with NAFLD had similar prevalence of left ventricular hypertrophy compared to patients without NAFLD, but a higher prevalence of diastolic dysfunction (62.5 vs 21.1%, P < 0.001), as defined by E/A ratio <1 and E-wave deceleration time >220 ms. Diastolic dysfunction (P = 0.040) and HOMA-IR (P = 0.012) remained independently associated with NAFLD at backward multivariate analysis. CONCLUSIONS: Non-alcoholic fatty liver disease was associated with insulin resistance and abnormalities of left ventricular diastolic function in a cohort of patients with essential hypertension, suggesting a concomitant increase of metabolic and cardiac risk in this condition.

[Two-years therapy with bosentan of pulmonary arterial hypertension related to connective tissue diseases]. / Due anni di terapia con bosentan dell'ipertensione arteriosa polmonare associata a connettiviti sistemiche.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a rare but severe complication of connective tissue diseases (CTD), with a negative impact on patients survival. Bosentan, a receptor antagonist of endothelin, has been proved effective for the treatment of PAH. The aim of this study was to evaluate the effects and the safety of bosentan administered for 2 years in a group of patients with PAH related to CTD. METHODS: Twelve patients with PAH related to systemic sclerosis (8 cases), SLE (2 cases), mixed connective tissue disease (1 case) and polymyositis (1 case) attending the Rheumatology Unit of Padova University were treated with bosentan for two years. Distance walked in 6 minutes, right ventricular systolic pressure and mean pulmonary artery pressure estimated by doppler echocardiography were evaluated at baseline and after 6, 12, 18 and 24 months of treatment. Safety was assessed by laboratory tests performed every two months. RESULTS: During bosentan treatment, a significant decrease of right ventricular systolic pressure was observed after 6, 12, 18 and 24 months in comparison to baseline, whereas pulmonary artery mean pressure remained unchanged. Distance walked in 6 minutes slightly increased after 6 and 12 months, but significantly decreased after 18 and 24 months, mostly because complications of CTD which compromised the ability to walk arose in 4 patients. Adverse events related to bosentan were observed in 2 cases. CONCLUSIONS: Bosentan has been demonstrated effective in reducing pulmonary arterial pressure in a two-year period of treatment. Exercise capacity improved only in the first year of therapy and worsened thereafter, suggesting the opportunity of a combination therapy for a long-term treatment of PAH related to CTD.

Coronary Microvascular Dysfunction Predicts Long-Term Outcome in Simultaneous Pancreas-Kidney Transplantation.

BACKGROUND: Patients with diabetes are at increased cardiovascular risk. Simultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice in patients with type 1 diabetes mellitus and diabetic nephropathy. We assessed coronary flow reserve (CFR) by transthoracic echocardiography as a marker of major adverse cardiac events (MACE) in SPKT patients. METHODS: We studied 48 consecutive SPKT patients (28 male, age at SPKT 54 ± 8 years). Time from transplantation was 8.5 ± 3 years. Follow-up was 4.6 ± 1.8 years. Coronary flow velocity in the left anterior descending coronary artery was detected by Doppler echocardiography at rest and during adenosine infusion. CFR was the ratio of hyperemic diastolic flow velocity (DFV) to resting DFV. A CFR ≤ 2 was considered abnormal and a sign of coronary microvascular dysfunction. MACE were cardiac death, myocardial infarction, and heart failure. RESULTS: CFR was 2.55 ± 0.8. CFR was ≤2 in 13 (27%) patients. CFR was lower in SPKT patients with MACE (2.1 ± 0.7 vs 2.7 ± 0.8, P = .03) and patients with MACE had a higher incidence of CFR ≤ 2 (P = .03). Time from transplantation was shorter in patients with MACE (P < .0001). Patients with CFR ≤ 2 had a lower MACE-free survival (P = .03). CFR ≤ 2 predicted the risk of MACE (P = .007) independently from coronary artery disease and metabolic control. However, this predicted role is lost when adjusted for the time from transplantation, which plays a protective role (P = .001). CONCLUSIONS: In SPKT, CFR ≤ 2 may be a reliable marker for MACE, independent of coronary artery disease diagnosis. However, this role seems to be reduced over time. This finding suggests a gradual reduction of cardiovascular risk in SPKT patients.

Skin cancer in heart transplant recipients: risk factor analysis and relevance of immunosuppressive therapy.

BACKGROUND: The frequency of skin tumors of all types and specifically of squamous cell carcinoma (SCC) is increased in heart transplantation (HT), but the predisposing risk factors are controversial. METHODS AND RESULTS: We studied 300 patients (age 49+/-15 years, 258 men, mean follow-up 4.6 years, follow-up range 1 month to 12 years) who were receiving standard double (cyclosporin plus azathioprine) or triple (cyclosporin plus azathioprine plus prednisone) therapy. The first-year rejection score was calculated for endomyocardial biopsy samples (International Society for Heart and Lung Transplantation grade 0=0, 1A=1, 1B=2, 2=3, 3A=4, 3B=5, and 4=6) and used as an indirect marker of the level of immunosuppression. Multivariate analysis (Cox regression) included age at HT, sex, skin type, first-year rejection score, presence of warts and solar keratosis, lifetime sunlight exposure, and first-year cumulative dose of steroids. The incidence of skin tumors of all types increased from 15% after 5 years to 35% after 10 years after HT according to life-table analysis. Age at HT of >50 years (P:=0.03, RR=5.3), skin type II (P:=0.05, RR=2.6), rejection score of 19 (P:=0.003, RR=5.7), solar keratosis (P:=0.001, RR=6.9), and lifetime sunlight exposure of >30 000 hours (P:=0.0003, RR=7.6) were risk factors for SCC. CONCLUSIONS: Older age at HT, light skin type, solar keratosis, greater sunlight exposure, and high rejection score in the first year were independently associated with an increased risk of SCC. The progressive increase in cancer frequency during follow-up and the association with high rejection scores suggest that both the length and level of immunosuppression may be relevant. Because cumulative immunosuppressive load is cumbersome to calculate, a high rejection score in the first year may provide a useful predictor for patients at risk.

Disrupted resting-state functional connectivity in progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Studies on functional connectivity in progressive supranuclear palsy have been restricted to the thalamus and midbrain tegmentum. The present study aims to evaluate functional connectivity abnormalities of the subcortical structures in these patients. Functional connectivity will be correlated with motor and nonmotor symptoms of the disease. MATERIALS AND METHODS: Nineteen patients with progressive supranuclear palsy (mean age, 70.93 ± 5.19 years) and 12 age-matched healthy subjects (mean age, 69.17 ± 5.20 years) underwent multimodal MR imaging, including fMRI at rest, 3D T1-weighted imaging, and DTI. fMRI data were processed with fMRI of the Brain Software Library tools by using the dorsal midbrain tegmentum, thalamus, caudate nucleus, putamen, and pallidum as seed regions. RESULTS: Patients had lower functional connectivity than healthy subjects in all 5 resting-state networks, mainly involving the basal ganglia, thalamus, anterior cingulate, dorsolateral prefrontal and temporo-occipital cortices, supramarginal gyrus, supplementary motor area, and cerebellum. Compared with healthy subjects, patients also displayed subcortical atrophy and DTI abnormalities. Decreased thalamic functional connectivity correlated with clinical scores, as assessed by the Hoehn and Yahr Scale and by the bulbar and mentation subitems of the Progressive Supranuclear Palsy Rating Scale. Decreased pallidum functional connectivity correlated with lower Mini-Mental State Examination scores; decreased functional connectivity in the dorsal midbrain tegmentum network correlated with lower scores in the Frontal Assessment Battery. CONCLUSIONS: The present study demonstrates a widespread disruption of cortical-subcortical connectivity in progressive supranuclear palsy and provides further insight into the pathophysiologic mechanisms of motor and cognitive impairment in this condition.

Neuroimaging evidence of gray and white matter damage and clinical correlates in progressive supranuclear palsy.

To evaluate gray matter (GM) and white matter (WM) abnormalities and their clinical correlates in patients with progressive supranuclear palsy (PSP). Sixteen PSP patients and sixteen age-matched healthy subjects underwent a clinical evaluation and multimodal magnetic resonance imaging, including three-dimensional T1-weighted imaging and diffusion tensor imaging (DTI). Volumetric and DTI analyses were computed using SPM and FSL tools. PSP patients showed GM volume decrease, involving the frontal cortex, putamen, pallidum, thalamus and accumbens nucleus, cerebellum, and brainstem. Additionally, they had widespread changes in WM bundles, mainly affecting cerebellar peduncles, thalamic radiations, corticospinal tracts, corpus callosum, and longitudinal fasciculi. GM volumes did not correlate with WM abnormalities. DTI indices of WM damage, but not GM volumes, correlated with clinical scores of disease severity and cognitive impairment. The neurodegenerative changes that occur in PSP involve both GM and WM structures and develop concurrently though independently. WM damage in PSP correlates with clinical scores of disease severity and cognitive impairment, thus providing further insight into the pathophysiology of the disease.

Plasma markers of endothelial dysfunction in pulmonary hypertension.

STUDY OBJECTIVES: To evaluate and to correlate endothelial cell dysfunction, using recently available plasma markers, with the magnitude of pulmonary artery pressure in patients with severe pulmonary hypertension (PH). DESIGN: Selected plasma markers of endothelial cell dysfunction were studied: nitric oxide (NO), thrombomodulin, tissue factor pathway inhibitor, and soluble endothelium, leukocyte, and platelet selectins (sE-, sL-, sP-selectins, respectively). SETTING: Padova University Hospital and Department of Pathology and Pharmacology, Loyola University of Chicago, Chicago, IL. PATIENTS: Fifteen patients had severe PH (four men and 11 women; mean age, 49.7 +/- 2.9 years: seven patients had primary pulmonary hypertension [PPH] and eight patients had secondary pulmonary hypertension [SPH]), and 20 patients were healthy control subjects. MEASUREMENT AND RESULTS: In patients with PH, sP- and sE-selectins were elevated, whereas sL-selectin was lower in comparison with the selectin levels in control subjects. However, the differences between patients with PH and control subjects were significant only for sL-selectin (p < 0.0001) and sE-selectin (p < 0.03). The NO level was significantly lower in patients with PH compared with the NO level in control subjects (p < 0.01). No difference in tissue factor pathway inhibitor level was noted between control subjects and patients with PH. Only a weak correlation was found between thrombomodulin plasma levels and magnitude of systolic pulmonary artery pressure (r = -0.528, p < 0.05). CONCLUSIONS: Our data are in keeping with the evidence for significant endothelial cell dysfunction in patients with PH and the need for chronic anticoagulation believed to increase survival in these patients. In addition, these data seem to suggest a need for newer agents that are able to increase the antithrombotic endothelial function.

Sulfinpyrazone reduces cyclosporine levels: a new drug interaction in heart transplant recipients.

BACKGROUND: Management of cyclosporine (CsA)-associated hyperuricemia in heart transplantation (HT) is difficult. Because of the myelotoxicity of combined allopurinol and azathioprine, we tested sulfinpyrazone. METHODS: We studied 120 HT recipients (109 men; mean age at HT, 52+/-10 years). All had received allopurinol for at least 6 months, which was stopped for 1 month before initiation of sulfinpyrazone. Mean follow-up from HT to onset of sulfinpyrazone (200 mg/day) was 59+/-41 months. We stopped the drug after 6+/-2 months. We compared CsA level and daily dose, serum creatinine, blood urea, and uric acid at onset and before interruption of sulfinpyrazone and, as control, in the last 6 months of allopurinol. RESULTS: Mean uricemia decreased with allopurinol (0.58+/-0.12 vs. 0.41+/-0.07 mmol/liter, p = 0.0001) as well as with sulfinpyrazone (0.51+/-0.13 vs. 0.40+/-0.12 mmol/liter, p = 0.0001). Mean creatinine increased (171+/-42 and 164+/-35 micromol/liter, p = 0.01) with allopurinol, whereas it tended to decrease with sulfinpyrazone (160+/-35 and 154+/-48 micromol/liter, p = NS). Mean urea did not change with allopurinol (14+/-5 vs. 15+/-7 mmol/liter, p = NS), but fell with sulfinpyrazone (14.01+/-5 vs. 12.60 +/-5 mmol/liter, p = 0.0004). Mean CsA levels were constant with allopurinol (193+/-73 vs. 188+/-65 ng/ml, p = NS), although CsA dose was slightly reduced (2.7+/-0.8 vs. 2.6+/-0.8 mg/kg/day, p = 0.007). Conversely, CsA levels dropped with sulfinpyrazone (183+/-89 vs. 121 +/-63 ng/ml, p = 0.0001) despite an increase in CsA daily dose (2.6 +/-0.9 vs. 2.8+/-0.9 mg/kg/day, p = 0.0001). Two subjects were treated for acute rejection. We observed no other side effects. In HT recipients sulfinpyrazone, as an alternative to allopurinol, is effective in achieving metabolic control of hyperuricemia. However, this drug reduced CsA levels, thus the risk of rejection is present.

Skin cancer in heart transplant recipients: frequency and risk factor analysis.

BACKGROUND: The frequency of skin cancer is increased among organ transplant recipients, but the predisposing risk factors are controversial. It is also unclear whether heart transplant patients face an increased risk compared to recipients of other organs, e.g. kidney transplants. METHODS: We performed univariate and multivariate analysis of risk factors for skin cancer in 252 heart transplants and in a control series of 228 kidney transplants followed up at a single center. An extensive dermatologic examination was carried out; baseline features, type of immunosuppression, number of 3A rejection episodes, extent of sunlight exposure and skin type were recorded. Multivariate analysis (Cox regression) included: age at transplantation, sex, skin type (Fitzpatrick's criteria), presence of solar keratosis, presence of warts, type of organ, sunlight exposure. RESULTS: During follow up skin cancer was more common among heart transplants (40, 16 %) than in kidney transplants (16, 7%, p = 0.004). The cumulative incidence of skin cancer by life table analysis increased from 16% after 5 years to 33% after 10 years in heart transplant patients and from 6% to 17% in kidney transplants (p 10000 hours (relative risk = 2.8), but not organ type were significant risk factors. CONCLUSION: Age at transplant, skin type and sunlight exposure, but not type of organ and type of immunosuppressive regimen, are associated with increased risk of skin cancer in heart transplantation.

Everolimus prevents coronary microvasculopathy in heart transplant recipients with normal coronary angiograms: an anatomo-functional study.

BACKGROUND: Coronary allograft vasculopathy (CAV) involves both epicardial vessels and coronary microcirculation. Little is known about the effect of everolimus on coronary microvasculopathy in heart transplantation (HT). The aim of our study was to assess the pathological substrate of coronary flow reserve (CFR) impairment in HT patients and the effect of everolimus on microvascular remodeling and CFR. METHODS: We studied 28 HT patients with normal coronary angiograms (25 male, age at HT 54±10 years). Immunosuppressive regimen consisted of cyclosporine and everolimus (10 patients) or mycophenolate mophetil (18 patients). They were evaluated with digital microscopy for morphometric analysis of fibrosis and microvascular remodeling. Coronary flow velocity in the left anterior descending coronary artery was detected using transthoracic Doppler echocardiography at rest and during adenosine infusion. CFR was the ratio of hyperaemic diastolic flow velocity (DFV) to resting DFV. A CFR≤2.5 was considered abnormal and sign of coronary microvascular dysfunction. RESULTS: In patients with CFR≤2.5 the thickness of the tunica media of intramyocardial arterioles was greater than in patients with CFR>2.5 (39±2 vs 17±3 µm; P=.02). Microvascular remodeling was significantly higher in patients with CFR≤2.5 (72.7±2.4 vs 50.4±8.4%; P<.007). Capillary density and fibrosis were comparable between groups (157.2±42.4 vs 175.7±42.4 capillaries/mm2; P=.3; and 6.8±5 vs 8.3±4.9%; P=.4, respectively). The thickness of the tunica media of intramyocardial arterioles was lower in patients whose therapy included everolimus (15±2 vs 32±4 µm, P=.03) and CFR was higher (3.2±0.5 vs 2.8±0.9; P=.03). CONCLUSION: The pathological substrate of reduced CFR in HT patients seems to be a hypertrophic remodeling of coronary arterioles. Everolimus appears to prevent such microvascular remodeling and preserve coronary flow reserve.

A transverse and longitudinal MR imaging voxel-based morphometry study in patients with primary cervical dystonia.

BACKGROUND AND PURPOSE: Findings of standard MR imaging examinations are usually normal in primary CD. These findings are now increasingly challenged by studies using advanced neuroimaging techniques detecting abnormalities in brain areas that may be functionally involved in the pathophysiology of CD. Our purpose was to evaluate GM volumes in patients with CD at baseline and 5 years later. MATERIALS AND METHODS: We enrolled 19 patients (F/M = 15:4, mean age = 53.2 + 11.2 years), 12 of whom were studied at baseline and again approximately 5 years later. Twenty-eight healthy volunteers acted as controls (F/M = 17:11, mean age = 47.5 + 15.6 years). The subjects were imaged with a 1.5T scanner by using a 3D T1-weighted sequence on 150 contiguous axial 1-mm-thick sections to apply VBM. RESULTS: At entry, VBM analysis disclosed significantly lower GM volumes in the left caudate head and putamen and in the premotor and primary sensorimotor cortices bilaterally in patients than in controls. No correlation was found between decreased GM volumes and patient age, severity of dystonia, or disease duration. At the 5-year follow-up, GM volumes in the left primary sensorimotor cortex in patients had decreased significantly from baseline. CONCLUSIONS: The findings obtained at entry and after a 5-year follow-up consistently showed decreased caudate, putamen, and sensorimotor cortex GM volumes in patients with CD, and they probably play a pathophysiologic role in CD.