Nailfold capillaroscopic changes in patients with idiopathic pulmonary arterial hypertension and systemic sclerosis-related pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) represents one of the main clinical expressions of the vascular changes in systemic sclerosis (SSc). Lung microvascular changes can play a role in the pathogenesis of idiopathic PAH (IPAH) also. The aim of this study is to investigate the presence of capillaroscopic abnormalities in patients with IPAH and to evaluate the differences in capillary nailfold changes between patients with IPAH and patients with SSc with and without PAH. METHODS: 39 SSc patients (19 with PAH - SSc-PAH and 20 without - SSc-noPAH), 21 subjects with IPAH and 20 healthy subjects were recruited. PAH was diagnosed by right heart catheterization. Nailfold videocapillaroscopy was performed (NVC) in all recruited subjects; capillary quantitative parameters (loops length and width, capillary density, neoangiogenesis) were evaluated and a semiquantitative scoring was used (normal, minor or major abnormalities for healthy controls and IPAH subjects and specific patterns - early, active and late - for SSc subjects) to define microvascular alterations. RESULTS: The presence of capillaroscopic abnormalities was detected in 38,1% subjects with IPAH; particularly, compared to healthy controls, capillary density was significantly lower (7,5±1,65loops/mm vs 9±1,37loops/mm p<0,05) and mean capillary width was significantly higher (21±13µm vs 17±3µm p<0,05). A more severe NVC pattern (active/late) was described. SSc-PAH patients compared to SSc-noPAH patients (73,2% vs 50% respectively, p<0,05), with a significantly lower capillary density (5,64±1,9loops/mm vs 6,5±1,3loops/mm p<0,05) and a significantly higher capillary width (55±7µm vs 35±8µm - p<0,05) and mean number of neoangiogenesis (N/mm) (1±0,33 vs 0,2±0,22 respectively p<0,05). CONCLUSIONS: These data, beyond to confirm the role of microvascular damage in SSc-related PAH, support the hypothesis of systemic microvascular involvement in IPAH also, which can be detected by NVC, although further studies are needed to establish whether the changes in the systemic microcirculation are causal or consequential to PAH.

Treatment with atorvastatin is associated with a better prognosis in chronic heart failure with systolic dysfunction: results from The Daunia Heart Failure Registry.

BACKGROUND: Few works have evaluated the effect of statins on left ventricular dysfunction in patients with chronic heart failure (CHF), by using tissue Doppler imaging (TDI). We therefore aimed to investigate whether atorvastatin treatment may influence prognosis and myocardial performance evaluated by TDI in subjects with CHF. METHODS: Five hundred thirty-two consecutive CHF outpatients enrolled in a local registry, the Daunia Heart Failure Registry, were prospectively analysed. 195 patients with CHF and left ventricular ejection fraction (LVEF) ≤40 %, either in treatment with atorvastatin (N: 114) or without statins (N: 81), underwent TDI examination. Adverse events were evaluated during follow-up. RESULTS: The atorvastatin group showed a lower incidence of adverse events (cardiac death: 0 % vs 7 %, p < 0.01), and better TDI performance (E/E' 15 ± 5.7 vs 18 ± 8.3, p < 001) than controls. Ischaemic CHF patients in treatment with atorvastatin also showed a lower incidence of adverse events (death: 10 % vs 26 %, p < 0.05; sustained ventricular arrhythmias: 5 % vs 19 %, p < 0.05, cardiac death: 0 vs 8 %, p < 0.05) and better TDI performance (E/E' ratio: 15.00 ± 5.68 vs 19.72 ± 9.14, p < 0.01; St: 353.70 ± 48.96 vs 303.33 ± 68.52 msec, p < 0.01) than controls. The association between atorvastatin and lower rates of cardiac death remained statistically significant even after correction in a multivariable analysis (RR 0.83, 95 % CI 0.71-0.96, p < 0.05 in CHF with LVEF ≤40 %; RR 0.77, 95 % CI 0.62-0.95, p < 0.05 in ischaemic CHF with LVEF ≤40 %). CONCLUSIONS: Treatment with atorvastatin in outpatients with systolic CHF is associated with fewer cardiac deaths, and a better left ventricular performance, as assessed by TDI.

Cardiopulmonary exercise test predicts sustained ventricular arrhythmias in chronic heart failure.

BACKGROUND: The cardiopulmonary exercise test (CPX) is an affordable tool for risk prediction in patients with chronic heart failure (CHF). We aimed to determine the role of CPX parameters in predicting the risk of incidence of sustained ventricular arrhythmias (SVA) in CHF. METHODS: Sixty-one consecutive patients with CHF enrolled in the Daunia Heart Failure Registry underwent CPX and were followed for 327 ± 247 days. Clinical follow-up was performed every month and anticipated in case of re-hospitalisation for cardiac disease. Incidence of SVA was evaluated by direct clinical examination (ECG, ambulatory ECG). RESULTS: Patients with episodes of SVA (N 14) showed lower values of pVO2 and PetCO2, and higher values of VE/VCO2, VE/VCO2 slope, and VE%. After correction for age, gender, diabetes, ischaemic heart disease and left ventricular ejection fraction, peak VO2 (hazard ratio (HR) 0.68, 95 % confidence interval (CI) 0.51-0.91, p < 0.05), VE% (HR 1.38, 95 % CI 1.04-1.84, p < 0.05), VE/VCO2 (HR 1.38, 95 % CI 1.04-1.82, p < 0.05), VE/VCO2 slope (HR 1.77, 95 % CI 1.31-2.39, p < 0.01), PetCO2 (HR 0.66, 95 % CI 0.50-0.88, p < 0.01) were found as predictors of SVA. At Kaplan-Meier analysis, lower event-free rates were found in subjects with peak VO2 values below median (log rank p < 0.05), values of VE/VCO2 above mean (p < 0.05), higher VE/VCO2 slope tertiles (p <0.05), and values of PetCO2 below median (p < 0.05). CONCLUSIONS: CPX provides prognostic independent information for risk of SVA in subjects with CHF.

Beta-blockers in pulmonary arterial hypertension: Time for a second thought?

Pulmonary arterial hypertension (PAH) is a heart failure syndrome characterized by right ventricular (RV) to pulmonary circulation uncoupling, counteracted by the sympathetic nervous system activation leading to ß1-receptors and α-myosin heavy chain downregulation, downregulation of the sarcoplasmic reticulum Ca2+ATPase, and ß-myosin heavy chain upregulation. Increased ventilation (VE) associated with VE inefficiency further characterizes PAH, as shown by an elevated VE versus carbon dioxide relationship slope during exercise, reflecting a specific behavior with progressive increase of dead space (VD) VE. The sympathetic system interacts with chemoreceptor-mediated VE control with increased VD leading to VE/perfusion mismatch. Growing evidence in the experimental models shows beneficial effects of different adrenoreceptor blockers on both right heart and pulmonary artery morphology and function. These effects can significantly change among ß-blockers according to their different pharmacokinetic and pharmacodynamic profiles. Since the first observation in the clinical setting, showing improvement associated with ß-blocker withdraw in PAH patients, recent studies suggest that the effects of ß-blockers in PAH might be related to the ß1-adrenergic receptors selectivity and α1- and ß3-related ancillary properties. While in the advanced stages of PAH ß-blockers may result deleterious as counteract the compensatory adrenergic-mediated effects of low cardiac output, in the early stages the modulation of the adrenergic system could ultimately improve VE efficiency and promote beneficial effects on heart failure gene expression and RV remodeling, particularly ß1-selective blockers and those associated with α- or ß3-activities. At present, all the above are physiologically sound but clinically unproven suggestions, and need to be tested in future randomized controlled trials.

Role of cardiopulmonary exercise test in the prediction of hemodynamic impairment in patients with pulmonary arterial hypertension.

Periodic repetition of right heart catheterization (RHC) in pulmonary arterial hypertension (PAH) can be challenging. We evaluated the correlation between RHC and cardiopulmonary exercise test (CPET) aiming at CPET use as a potential noninvasive tool for hemodynamic burden evaluation. One hundred and forty-four retrospective PAH patients who had performed CPET and RHC within 2 months were enrolled. The following analyses were performed: (a) CPET parameters in hemodynamic variables tertiles; (b) position of hemodynamic parameters in the peak end-tidal carbon dioxide pressure (PETCO2) versus ventilation/carbon dioxide output (VE/VCO2) slope scatterplot, which is a specific hallmark of exercise respiratory abnormalities in PAH; (c) association between CPET and a hemodynamic burden score developed including mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index, and right atrial pressure. VE/VCO2 slope and peak PETCO2 significantly varied in mPAP and PVR tertiles, while peak oxygen uptake (peak VO2) and O2 pulse varied in the tertiles of all hemodynamic parameters. PETCO2 versus VE/VCO2 slope showed a strong hyperbolic relationship (R 2 = 0.7627). Patients with peak PETCO2 > median (26 mmHg) and VE/VCO2 slope < median (44) presented lower mPAP and PVR (p < 0.005) than patients with peak PETCO2 < median and VE/VCO2 slope > median. Multivariate analysis individuated peak VO2 (p = 0.0158) and peak PETCO2 (p = 0.0089) as hemodynamic score independent predictors; the formula 11.584 - 0.0925 × peak VO2 - 0.0811 × peak PETCO2 best predicts the hemodynamic score value from CPET data. A significant correlation was found between estimated and calculated scores (p < 0.0001), with a precise match for patients with mild-to-moderate hemodynamic burden (76% of cases). The results of the present study suggest that CPET could allow to estimate the hemodynamic burden in PAH patients.

Controversies in echocardiography: 2D vs 3D vs 4D.

In the latest years several manuscripts have showed some new possible advantages of the three-dimensional (3D) echocardiography in daily practice. 3D echocardiography allows imaging and analysis of cardiovascular structures as they move in time and space, thus creating possibility for creation of 4D datasets (3D and real-time). Real-time three-dimensional echocardiography (RT3DE) is a major innovation in the history of cardiovascular ultrasound. Advances in computer and transducer technologies, especially the fully-sampled matrix array transducer, have permitted real-time 3D image acquisition and display. The aim of this manuscript is to give a brief review of the development of the 3D echocardiography and of comparison of two-dimensional echocardiography versus 3D echocardiography and RT3DE.

Effect of a Low Glycemic Index Mediterranean Diet on Non-Alcoholic Fatty Liver Disease. A Randomized Controlled Clinici Trial.

INTRODUCTION: Non-Alcoholic Fatty Liver Disease (NAFLD) is currently the most common form of liver disease worldwide affecting all ages and ethnic groups and it has become a consistent threat even in young people. Our aim was to estimate the effect of a Low Glycemic Index Mediterranean Diet (LGIMD) on the NAFLD score as measured by a Liver Ultrasonography (LUS). DESIGN: NUTRIzione in EPAtologia (NUTRIEPA) is a population-based Double-Blind RCT. Data were collected in 2011 and analyzed in 2013-14. SETTING/PARTICIPANTS: 98 men and women coming from Putignano (Puglia, Southern Italy) were drawn from a previous randomly sampled population-based study and identified as having moderate or severe NAFLD. INTERVENTION: The intervention strategy was the assignment of a LGIMD or a control diet. OUTCOME MEASURES: The main outcome measure was NAFLD score, defined by LUS. RESULTS: After randomization, 50 subjects were assigned to a LGIMD and 48 to a control diet. The study lasted six months and all participants were subject to monthly controls/checks. Adherence to the LGIMD as measured by Mediterranean Adequacy Index (MAI) showed a median of 10.1. A negative interaction between time and LGIMD on the NAFLD score (-4.14, 95% CI -6.78,-1.49) was observed, and became more evident at the sixth month (-4.43, 95%CI -7.15, -1.71). A positive effect of the interaction among LGIMD, time and age (Third month: 0.07, 95% CI 0.02, 0.12; Sixth month: 0.08, 95% CI 0.03,0.13) was also observed. CONCLUSIONS: LGIMD was found to decrease the NAFLD score in a relatively short time. Encouraging those subjects who do not seek medical attention but still have NAFLD to follow a LGIMD and other life-style interventions, may reduce the degree of severity of the disease. Dietary intervention of this kind, could also form the cornerstone of primary prevention of Type 2 Diabetes Mellitus (T2DM) and cardiovascular disease.

Immunohistochemical and serological 90K/Mac-2BP detection in hepatocellular carcinoma patients: different behaviour of two monoclonal antibodies.

To clarify the biological role of the 90K/Mac-2BP glycoprotein, we evaluated the ability of two MAbs SP-2 and 1A4.22, to reveal this glycoprotein in both serum and tissue from hepatocellular carcinoma (HCC) patients. Tissue expression of 90K was detected by the immunohistochemical method in 20 HCC patients, while the 90K serum level was assessed by the ELISA assay in 13 HCC patients. MAb SP-2 was reactive only in serum, with a mean value of 12.8+/- 6.7 microg/ml . On the contrary, MAb 1A4.22 revealed immunoreactivity both in 92% of sera and in 60% of neoplastic samples. Positive staining was seen only in the epithelial cells and was cytoplasmic and granular in all instances. The mean 90K serum level assayed with MAb 1A4.22 was 29.4 +/- 13.7 microg/ml. Patients with a 90K serum level 30 microg/ml. Moreover, a possible poor prognostic role was observed for negative 90K in tissue. Our results suggest that only MAb 1A4.22 could demonstrate 90K glycoprotein expression in paraffin-embedded tissue and that this MAb could have a diagnostic and prognostic role in both sera and tissues from HCC patients.

Association of pS2 (TFF1) release with breast tumour proliferative rate: in vitro and in vivo studies.

Although cytosolic expression of the protein pS2 (TFF1) is considered to be a marker of oestrogen receptor (OR) function, there exists some clinical data to suggest an inverse relationship of cytosolic pS2 to tumour proliferation. Although secreted from breast cancer cells, the relationship of pS2 secretion to tumour natural history has been little studied. The mechanisms and kinetics of pS2 release and its relation to tumour cell proliferation were studied in a human breast cancer cell line MCF-7 and verified in a preliminary clinical study. Stimulation by stripped serum or oestradiol resulted in parallel increases of proliferation and pS2 release in both time course and dose-response experiments. Direct pharmacological alterations of proliferation were followed by identical changes in pS2 release. The relationship between serum pS2 levels and tumour proliferative activity when analysed as a function of steroid status showed a slope of 0.56 in OR+ vs. 0.19 in OR- tumours. It is concluded that pS2 release from breast cancer cells is associated with their proliferation and measurement of serum pS2 levels might be a good predictor of tumour proliferative state and could permit noninvasive monitoring of this tumour parameter.

Differential responsiveness of proliferation and cytokeratin release to stripped serum and oestrogen in the human breast cancer cell line, MCF-7.

In vitro research into hormone sensitivity and the relation to proliferation of cytokeratin release from cancer cells is scarce. Therefore, we examined the stimulation of proliferation and the release of cytokeratins in a breast cancer cell culture model. Cell growth was stimulated by 17 beta-oestradiol (10(-11) M), stripped serum (10%) and by the two together. Cytokeratin release was stimulated only by stripped serum, oestradiol having no effect. After long incubation periods (> 12 h), cytokeratin release also commenced in the control and oestradiol treatments. Release rate versus time analysis suggested that there are two different release processes. Cytokeratin release was first stimulated at a stripped serum concentration approximately 100 times lower than that which initiated proliferation. Pharmacological alteration of proliferation with cordyceptin resulted in growth changes without alterations in cytokeratin release. We conclude that cytokeratin release in these cells is unrelated to proliferation, independent of oestrogen action and probably in some way related to growth factor receptor function.

Cytokeratins and proliferation in breast cancer patients.

Tissue polypeptide antigen (TPA) was studied in 242 sera and 165 tumor cell cytosols (both evaluations in 67 cases) of breast cancer patients, for which proliferative activity, determined by the TLI technique, was also available. The TPA serum and tumor cell cytosol median values (utilized for measure analysis as cut-off) were 70 U/1 and 377 U/mg cytosol protein, respectively. High serum TPA levels were associated with unfavourable clinicopathological characteristics whereas a higher tumor cell cytosol TPA level was associated with better cytohistological tumor differentiation. Furthermore, no overall correlation was found between serum and tumor cell cytosol TPA levels or between their levels and TLI. When analyzing cases in which serum and tumor cell cytosol TPA values were higher than 100 U/l and 500 U/mg cytosol protein, respectively (n = 28), serum TPA was positively associated with TLI (slope = 12.3 r = 0.55, p < 0.01), while cytosolic TPA resulted negatively associated with TLI (slope = -87.4 r = 0.41, p < 0.01). Finally, a strong inverse relationship between cytosolic and serum TPA (p < 0.0005) became evident. We suggest that TPA could represent a serum marker for tumor cell proliferation in specific patient subgroups with original high serum and/or cytosol TPA expression.

Evaluation of phagocytic-activity in neoplastic patients treated with subcutaneous recombinant IL-2.

Immunostimulating and immunosuppresive events have been noted during rIL-2 immunotherapy and cell-mediated immune deficiencies have been reported in the neutrophil and monocyte functions, determining a high incidence of infections in patients during intravenous rIL-2 treatment. The phagocytic activity of monocytes/macrophages and granulocytes was evaluated in 10 advanced solid tumor patients treated with subcutaneous rIL-2. Several indirect parameters of phagocytosis were also considered, such as Neopterin, Beta2 microglobulin, IL-2 soluble receptor, and the C3 and C4 fractions of the complement system. A decreased phagocytosis was demonstrated after subcutaneous rIL-2 administration together with an increase of indirect parameters of granulocyte/macrophage activity. Therefore, cellular activation does not seem to correspond to actual phagocytosis which is probably due to IL-2-induced secondary cytokines or to rIL-2 inhibitory effects.

Gelatinase-a/mmp-2 serum levels and neoplastic progression in breast-cancer patients.

The metastatic potential of cancer cells has been associated to their ability to elaborate and secrete basement membrane degradative enzymes. In this process a major role appears to be played by a protease known as gelatinase A (72 kDa type IV collagenase, MMP-2). In an effort to assess the significance of these findings to breast cancer progression, we have evaluated the gelatinase A/MMP-2 serum levels in a cohort of 80 breast cancer patients, 27 subjects affected by benign breast disease and 27 healthy controls. Although differences between the three groups were observed, with the highest values monitored in benign breast disease, they were not statistically significant. On the contrary, within the breast cancer cohort, the patients presenting clinical evidence of distant metastases (M+, n=40) had statistically elevated enzyme serum levels (p<0.03) compared to those without nodal involvement and distant metastases (N-M-, n=20). The statistical significance was still evident when considering the overall M- cohort (including N+ and N- patients, n=40) compared to the M+. Although indicating that, in general, gelatinase A/MMP-2 is not a useful serum marker for breast cancer screening and diagnosis, the findings point toward its involvement in the breast cancer metastatic process and suggest a possible value in monitoring the outcome of the disease.

Subcutaneous ril-2 in advanced melanoma and kidney carcinoma.

The aim of the present study was to verify the efficacy and tolerability of a treatment protocol using subcutaneous administration of rIL-2. Eighteen patients with metastatic disease were treated: 10 with renal carcinoma and 8 with malignant melanoma. The drug was administered as follows: 9 million UI/mq twice daily for two days followed by 1.8 million UI/mq twice daily for five days/week for six consecutive weeks. Of the 15 patients evaluated for clinical response, all completed treatment without rIL-2 dose modifications. No complete response was obtained. One patient with malignant melanoma and 1 with renal carcinoma (13%) had partial response (soft tissue and lymph nodes respectively) which lasted 3 and 4 months. Six patients with renal carcinoma and 3 melanoma patients had stable disease (60%) which lasted 6 months (median). Toxicity was moderate and spontaneously reversing after stopping treatment. Haemato-immunological modifications and pharmacokinetic study of this modality of rIL-2 treatment were also examined.

Helicobacter pylori is associated with modified lipid profile: impact on Lipoprotein(a).

OBJECTIVES: Helicobacter pylori is a controversial risk factor for atherosclerosis. We investigated whether the bacterium persistent inflammation or the expression of the cytotoxin-associated gene A (CagA) may affect serum lipids as well as Lipoprotein(a). DESIGN AND METHODS: Two hundred-eleven healthy volunteers were evaluated for lipids and Lipoprotein(a). Helicobacter pylori was characterized by Urea Breath Test and IgG-anti-CagA. apo(a) Kringle-IV polymorphism was genotyped. RESULTS: Prevalence of the infection was 72%; 43% of subjects expressed CagA reactivity. Infected subjects showed increased levels of cholesterol, LDL-cholesterol, and cholesterol/HDL-cholesterol atherogenic index. Association with the Helicobacter pylori CagA(-) strains persisted after the adjustment for covariates. Significant difference between infected and uninfected subjects was found in Lipoprotein(a) levels. This difference did not arise from the Kringle-IV genotype. CONCLUSIONS: The infection per se significantly modified serum lipid and Lipoprotein(a) concentrations. CagA does not seem to be a reliable marker of pathogenicity for the atherogenic complications of H. pylori infection.

Comparison of nuclear matrix protein 22 and bladder tumor antigen in urine of patients with bladder cancer.

Recently, two new tumor markers for bladder cancer have been introduced: NMP22 test and BTA TRAK assay. This study was designed to evaluate the urinary values of these two proteins using quantitative enzyme immunoassays in well microplates. Urine samples from 47 healthy subjects, 26 with benign genitourinary disorders and 109 patients with a histological diagnosis of bladder cancer were collected. The specificity, the positive predictive value, the negative predictive value and the efficiency were established for NMP 22 and BTA, and the cut off values were fixed at a specificity of 95% in the benign disease group (12 U/ml and 23 U/ml respectively). We observed a very high concordance between the two urinary tumor markers (73%), although the overall sensitivity of BTA in bladder cancer patients seems to be better than that of NMP22 (62% vs 54% respectively), especially in the superficial disease group (36% for BTA and 14% for NMP22).

Serum 90K/MAC-2BP glycoprotein levels in hepatocellular carcinoma and cirrhosis.

90K/MAC-2BP glycoprotein is a serum tumour marker, member of the scavenger receptor cysteine rich (SRCR) protein superfamily, involved in different immunological mechanisms. In the present study, we determined 90K serum levels by a sandwich enzyme immunoassay using the same monoclonal antibody in 11 chronic active hepatitis (CAH), 48 liver cirrhosis and 36 hepatocellular carcinoma (HCC). In comparison, the same samples were also tested for AFP. According to a cut-off point of 14 micrograms/mL for the 90K, established as 100% of specificity in 50 controls, we observed increasing positivities from CAH to cirrhosis and then to HCC (27%, 50% and 78%, respectively). In cirrhotic patients 90K levels were associated with the presence of anti-HCV antibodies, but not with the degree of liver compromise. Finally, 90K sensitivity was higher than AIFP in all groups of hepatic patients. However, further investigations are needed before proposing 90K as a clinical useful tumour marker in the progression from cirrhosis to HCC.

Are 90K/MAC-2BP serum levels correlated with poor prognosis in HCC patients? Preliminary results.

In this study we assessed the prognostic significance of 90K/MAC-2BP serum levels in a group of 40 hepatocellular carcinoma patients. This glycoprotein is a new, interesting serum marker that reflects the immune reaction of the host against certain viral infections and tumors such as breast, ovarian and pancreatic cancer. Hepatocellular carcinoma (HCC) is one of the most widespread tumors in the world. AFP is currently the most useful marker for HCC, in spite of its poor diagnostic sensitivity. In this study 40 cirrhotic HCC patients were enrolled. The prevalence of viral hepatic infections in this group was 73% for HCV, 8% for HBV, and 8% for both viruses. Thirteen percent of the patients showed non-virus-related liver damage. 90K serum levels were assayed by an ELISA kit and AFP levels by a chemiluminescent enzyme immunometric system. The overall survival curves were estimated by the Kaplan-Meier method, taking into account age, sex, 90K and AFP serum levels. Statistical analysis showed a highly significant influence on overall survival of age below 70 years and 90K serum levels below the cutoff of 14 ng/mL. Serum AFP (< or = 20 ng/mL) had positive prognostic value only when it was associated with 90K levels (p < 0.02, log-rank).