Anna Chiara Frigo

Quantitative assessment of endomyocardial biopsy in arrhythmogenic right ventricular cardiomyopathy/dysplasia: an in vitro validation of diagnostic criteria

AIMS To provide a standardized endomyocardial biopsy (EMB) protocol and diagnostic quantitative parameters for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). The Task Force criteria for the in vivo diagnosis of ARVC/D include tissue characterization by EMB as a major criterion. METHODS AND RESULTS EMBs were simulated in vitro with a Cordis bioptome in explanted hearts from six groups: diffuse (n = 10) and segmental (n = 10) ARVC/D, dilated cardiomyopathy (DC) (n = 10), controls (n = 10), adipositas cordis (n = 10), elderly >80 years (n = 10). Sampling sites were the RV inferior-subtricuspid, antero-apical, and mid-outflow tract (RVOT), the septum, and the left ventricle (LV). Histomorphometry was performed to evaluate the amount of myocardium and fibrous and fatty tissues. Myocyte diameters and abnormalities were also assessed. By selecting a 95% specificity, the ARVC/D diagnostic cut-offs on cumulative RV EMB samples are myocardium <59%, fibrosis >31% and fat >22% (80, 50, and 50% sensitivity, respectively). By excluding elderly and obese people groups a lower cut-off for fat was found (>9%). A high variability between different RV sampling sites was observed; the antero-apical was the most informative region although fat at this level is non-specific. No useful diagnostic cut-off for fatty tissue was identified at the antero-apical and RVOT area. No significant difference was found for any tissue parameter either in septal or in LV EMB. Increased RV myocyte diameters and cytological changes were detected in ARVC/D and DC. CONCLUSION The residual myocardium is the main diagnostic morphometric parameter in ARVC/D, whereas fat at the apex is non-specific. Sensitivity and specificity vary according to the RV region. Target sampling of the triangle of dysplasia is required, although only a single region is often informative, emphasizing the usefulness of imaging-guided EMB. There is no diagnostic value of either septal or LV EMB. Cardiomyopathic changes of the myocytes also appear important for establishing a pathological diagnosis.

Adalimumab Is More Effective Than Azathioprine and Mesalamine at Preventing Postoperative Recurrence of Crohn's Disease: A Randomized Controlled Trial

OBJECTIVES:Postsurgical recurrence of Crohns disease (CD) is very frequent and, to date, only infliximab has been shown to be useful in preventing it. The efficacy of adalimumab (ADA) is poorly known. We evaluated whether the administration of ADA after resective intestinal surgery reduces postoperative CD recurrence.METHODS:We randomly assigned 51 patients with CD who had undergone ileocolonic resection to receive after 2 weeks from surgery ADA at the dose of 160/80/40 mg every two weeks, azathioprine (AZA) at 2 mg/kg/day, or mesalamine at 3 g/day, and they were followed up for 2 years. The primary end point was the proportion of patients with endoscopic and clinical recurrence. Secondary end point was the assessment of quality of life by means of a previously validated questionnaire.RESULTS:The rate of endoscopic recurrence was significantly lower in ADA (6.3%) compared with the AZA (64.7%; odds ratio (OR)=0.036 (95% confidence interval (CI) 0.004–0.347)) and mesalamine groups (83.3%; OR=0.013 (95% CI 0.001–0.143)). There was a significantly lower proportion of patients in clinical recurrence in the ADA group (12.5%) compared with the AZA (64.7%; OR=0.078 (95% CI 0.013–0.464)) and mesalamine groups (50%; (OR=0.143 (95% CI 0.025–0.819)). The quality of life was higher in the ADA (202) than in the AZA (90; OR=0.028 (95% CI 0.004–0.196)) and mesalamine groups (98; OR=0.015 (95% CI 0.002–0.134)).CONCLUSIONS:The administration of ADA after intestinal resective surgery was greatly effective in preventing endoscopic and clinical recurrence of CD. Further larger studies are necessary to confirm the therapeutic advantage and to show the economic implications of biologic therapy in this field.

Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites

BACKGROUND & AIMS For several years hepatologists have defined acute renal failure in patients with cirrhosis as an increase in serum creatinine (sCr) ≥ 50% to a final value of sCr>1.5mg/dl (conventional criterion). Recently, the Acute Kidney Injury Network (AKIN) defined acute renal failure as acute kidney injury (AKI) on the basis of an absolute increase in sCr of 0.3mg/dl or a percentage increase in sCr ≥ 50% providing also a staging from 1 to 3. AKIN stage 1 was defined as an increase in sCr ≥ 0.3mg/dl or increase in sCr ≥ 1.5-fold to 2-fold from baseline. AKI diagnosed with the two different criteria was evaluated for the prediction of in-hospital mortality. METHODS Consecutive hospitalized patients with cirrhosis and ascites were included in the study and evaluated for the development of AKI. RESULTS Conventional criterion was found to be more accurate than AKIN criteria in improving the prediction of in-hospital mortality in a model including age and Child-Turcotte-Pugh score. The addition of either progression of AKIN stage or a threshold value for sCr of 1.5mg/dl further improves the value of AKIN criteria in this model. More in detail, patients with AKIN stage 1 and sCr<1.5mg/dl had a lower mortality rate (p=0.03), a lower progression rate (p=0.01), and a higher improvement rate (p=0.025) than patients with AKIN stage 1 and sCr ≥ 1.5mg/dl. CONCLUSIONS Conventional criterion is more accurate than AKIN criteria in the prediction of in-hospital mortality in patients with cirrhosis and ascites. The addition of either the progression of AKIN stage or the cut-off of sCr ≥ 1.5mg/dl to the AKIN criteria improves their prognostic accuracy.

Postconditioning during coronary angioplasty in acute myocardial infarction: the POST-AMI trial

BACKGROUND Postconditioning (PC) has been suggested to reduce myocardial damage during primary percutaneous coronary intervention (PPCI), nevertheless clinical experience is limited. We aimed to explore the cardioprotective effect of PC using cardiac magnetic resonance (CMR) in ST-elevation myocardial infarction (STEMI) patients treated by PPCI. METHODS A total of 78 patients with first STEMI (aged 59±12 years) referred for PPCI, were stratified for STEMI location and randomly assigned to conventional PPCI or PPCI with PC. All patients, with occluded infarct related artery and no collateral circulation, received abciximab intravenously before PPCI. After reperfusion by effective direct stenting, control subjects underwent no further intervention, while in treated patients PC was performed within 1 min of reflow by 4 cycles of 1-minute inflation and 1-minute deflation of the angioplasty balloon. Primary end-point was infarct size (IS) reduction, expressed as percentage of left ventricle mass assessed by delayed enhancement on CMR at 30±10 days after index PPCI. RESULTS All baseline characteristics but diabetes (p=0.06) were balanced between groups. Postconditioning patients trended toward a larger IS compared to those treated by standard PPCI (20±12% vs 14±10%, p=0.054). After exclusion of diabetics, PC group still showed a trend to larger IS (p=0.116). Major adverse events seem to be more frequent in PC group irrespective to diabetic status (p=0.053 and p=0.080, respectively). CONCLUSIONS This prospective, randomized trial suggests that PC did not have the expected cardioprotective effect and on the contrary it might harm STEMI patients treated by PPCI plus abciximab. (Clinical Trial Registration-unique identifier: NCT01004289).

Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death

Background— Mitral valve prolapse (MVP) may present with ventricular arrhythmias and sudden cardiac death (SCD) even in the absence of hemodynamic impairment. The structural basis of ventricular electric instability remains elusive. Methods and Results— The cardiac pathology registry of 650 young adults (⩽40 years of age) with SCD was reviewed, and cases with MVP as the only cause of SCD were re-examined. Forty-three patients with MVP (26 females; age range, 19–40 years; median, 32 years) were identified (7% of all SCD, 13% of women). Among 12 cases with available ECG, 10 (83%) had inverted T waves on inferior leads, and all had right bundle-branch block ventricular arrhythmias. A bileaflet involvement was found in 70%. Left ventricular fibrosis was detected at histology at the level of papillary muscles in all patients, and inferobasal wall in 88%. Living patients with MVP with (n=30) and without (control subjects; n=14) complex ventricular arrhythmias underwent a study protocol including contrast-enhanced cardiac magnetic resonance. Patients with either right bundle-branch block type or polymorphic complex ventricular arrhythmias (22 females; age range, 28–43 years; median, 41 years), showed a bileaflet involvement in 70% of cases. Left ventricular late enhancement was identified by contrast-enhanced cardiac magnetic resonance in 93% of patients versus 14% of control subjects (P<0.001), with a regional distribution overlapping the histopathology findings in SCD cases. Conclusions— MVP is an underestimated cause of arrhythmic SCD, mostly in young adult women. Fibrosis of the papillary muscles and inferobasal left ventricular wall, suggesting a myocardial stretch by the prolapsing leaflet, is the structural hallmark and correlates with ventricular arrhythmias origin. Contrast-enhanced cardiac magnetic resonance may help to identify in vivo this concealed substrate for risk stratification.

Barcelona Clinic Liver Cancer staging and transplant survival benefit for patients with hepatocellular carcinoma: a multicentre, cohort study

BACKGROUND Allocation of deceased-donor livers to patients with chronic liver failure is improved by prioritising patients by 5-year liver transplantation survival benefit. The Barcelona Clinic Liver Cancer (BCLC) staging has been proposed as the standard means to assess for prognosis of patients with hepatocellular carcinoma. We aimed to create a prediction model linking the BCLC stage of patients with hepatocellular carcinoma to their 5-year liver transplant benefit. METHODS A large cohort of consecutive patients with hepatocellular carcinoma (n=1328) from the ITA.LI.CA database (n=2951) were judged as potentially eligible for liver transplantation according to the following criteria: absence of macroscopic vascular invasion or metastases, age 70 years or younger, and absence of relevant extra-hepatic comorbidities. To assess the correlation between BCLC staging and non-liver transplantation survival, we did Cox univariate and multivariate analyses including the following covariates: BCLC stage, year of diagnosis, age, sex, cause of cirrhosis, model for end-stage liver disease score, α-fetoprotein concentrations, and treatment. Liver-transplantation survival benefit for patients was calculated, using Monte Carlo simulation analysis, as the patients 5-year life expectancy with liver transplantation (estimated by the Metroticket model) minus the 5-year life expectancy without liver transplantation according to BCLC stage. FINDINGS 83 (6%) of 1328 patients had BCLC 0 stage disease, 614 (46%) had BCLC A, 500 (38%) had BCLC B-C, and 131 (10%) had BCLC D. In the Cox non-liver transplantation survival multivariate model, hazard ratios associated with increasing BCLC stages were 1.530 (95% CI 1.107-2.116) for BCLC A versus BCLC 0, 1.572 (1.350-1.830) for BCLC B-C versus BCLC A, and 1.470 (1.164-1.856) for BCLC D versus BCLC B-C. Results of the Monte Carlo simulation analysis confirmed the significant effect of BCLC classification on transplant benefit; in the adjusted model, a median 5-year transplant benefit of 11.19 months (IQR 10.73-11.67) for BCLC 0, 13.49 months (11.51-15.57) for BCLC A, 17.36 months (15.06-19.28) for BCLC B-C, and 28.46 months (26.38-30.34) for BCLC D. INTERPRETATION Liver transplantation could result in survival benefit for patients with hepatocellular carcinoma and advanced liver cirrhosis (BCLC stage D) and in those with intermediate tumours (BCLC stages B-C), regardless of the nodule number-size criteria (ie, Milan criteria), provided that macroscopic vascular invasion and extra-hepatic disease are absent. FUNDING None.

Sleep apnoea syndrome is highly prevalent in acromegaly and only partially reversible after biochemical control of the disease

BACKGROUND Whether sleep apnoea syndrome (SAS) subsides after biochemical and clinical remission of acromegaly is controversial. OBJECTIVE To assess the presence of SAS in a cohort of acromegalic patients, which included a subgroup with active disease and a subgroup in remission, and to evaluate clinical and biochemical independent predictors of SAS. DESIGN Cross-sectional and longitudinal study. SETTING Italian university department of internal medicine. PATIENTS About 36 acromegalic patients: 18 active and 18 controlled. MEASUREMENTS Polysomnography was performed in all patients and repeated in six with active acromegaly and SAS after achieving disease control. Echocardiographic parameters were also measured. RESULTS The prevalence of SAS was 47% in the overall acromegalic population: 56% in the active group and 39% in the controlled one. In a multivariate analysis IGF1, male gender, age, body mass index, and disease duration were associated with SAS. Impaired glucose tolerance or diabetes was more prevalent in patients with SAS, particularly in the severe cases. Among the six patients of the longitudinal study, five showed improvement of SAS, but none recovered. No correlation was found between echocardiographic parameters and severity of SAS. CONCLUSION SAS can persist after recovery of acromegaly in several patients. Given the negative prognostic significance of this respiratory disorder, polysomnography should be included as routine procedure in the work-up of the acromegaly, even if in remission, being mandatory in those patients considered at high risk (elderly males, overweight, diabetic). Appropriate intensive treatment should be implemented to minimize the clinical impact of SAS in acromegaly.

Myocardial bridging, a frequent component of the hypertrophic cardiomyopathy phenotype, lacks systematic association with sudden cardiac death

AIMS The clinical significance attributable to myocardial bridging of left anterior descending coronary artery in hypertrophic cardiomyopathy (HCM) remains controversial. METHODS AND RESULTS Prevalence and depth of coronary artery bridges (CBs) were assessed in 255 hearts, including 115 with HCM (median age 29, range 5-90; 75% male), and 140 controls. Coronary artery bridges were more common in HCM (47/115; 41%) than in patients who died of a variety of non-HCM-related causes (21/100; 21%; P = 0.002), or in patients with congenital aortic stenosis and left ventricular (LV) hypertrophy (5/40; 12%; P = 0.001). Among the HCM hearts, CBs were present in 33 of 77 patients (43%) with sudden death, in 10 of 27 (37%) with heart failure death (or heart transplantation), and in 4 of 11 (36%) with other modes of death (P = 0.826). Deeply embedded CBs (> or =2 mm) occurred with similar frequency in HCM patients with sudden (21 of 77; 27%) or heart failure death (5 of 27; 13%; P = 0.191). In sudden death patients, the presence of CB was unrelated to gender (33% in women and 45% in men, P = 0.406) and age (41% <18 years vs. 44% > or =18 years; P = 0.827). CONCLUSION In this morphological analysis of more than 250 hearts, CBs are a frequent component of phenotypically expressed HCM, and more common than in other disorders with or without LV hypertrophy. Although no systematic association with HCM-related sudden death is evident, our findings do not exclude the possibility that CB could contribute to increased risk in some individual patients, potentially impacting management decision-making on a case-by-case basis.

Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer

The present study aimed at investigating whether the simultaneous evaluation of pharmacokinetic, pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy. One hundred and thirty consecutive, B2 and C Dukes stage colorectal cancer patients were prospectively enrolled. 5FU pharmacokinetics was evaluated at the first cycle. Thymidylate synthase (TYMS) 5′UTR and 3′UTR polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms were assessed in peripheral leukocytes. Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity, disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that: (a) low 5FU clearance was an independent predictive factor for severe toxicity (OR=7.32; P<0.0001); (b) high-5FU clearance predicted poorer DFS (HR=1.96; P=0.041) and OS (HR=3.37; P=0.011); (c) advanced age was associated with shorter DFS (HR=3.34; P=0.0008) and OS (HR=2.66; P=0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3–4 toxicity (P=0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome.

Predictors of low bone mineral density in the elderly: the role of dietary intake, nutritional status and sarcopenia

Objectives:The aims of this study were to investigate the relationship between sarcopenia, dietary intake, nutritional indices and hip bone mineral density (BMD) in the elderly, and to estimate the risk of low BMD due to specific independent predictor thresholds.Subjects and methods:Body mass index (BMI), serum albumin, energy and protein intake were studied in 352 elderly outpatients (216 women aged 73.5±5.3 years and 136 men aged 73.9±5.6 years). BMD at different hip sites and appendicular skeletal muscle mass (ASMM) were assessed by dual-energy X-ray absorptiometry.Results:The prevalence of osteoporosis was 13% in men and 45% in women, while the prevalence of sarcopenia (50%) and hypoalbuminemia (5%) were similar in both genders. BMI, albumin and ASMM were significantly associated with BMD in both genders: so was protein intake, but only in men. By multiple regression analysis, the variables that retained their independent explanatory role on total hip BMD, were BMI and protein intake in men, and BMI and albumin in women. By logistic regression analysis, men risked having a low BMD with a BMI <22 (OR=12) and a protein intake <65.7 g/day (OR=3.7). Women carried some risk already in the BMI 25–30 class (OR=5), and a much greater risk in the BMI <22 class (OR=26). Albumin <40 g/l also emerged as an independent risk factor (OR=2.6).Conclusions:BMI in both genders, albumin in women and protein intake in men have an independent effect on BMD. BMI values <22 are normal for younger adults but carry a higher risk of osteoporosis in the elderly, particularly in women. Age-related sarcopenia does not seem to be involved in bone mass loss.