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.

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.

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.

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.

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.

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.

Relationship among fatty liver, adipose tissue distribution and metabolic profile in moderately obese children: an ultrasonographic study.

We examined the relationship between moderate obesity and glucose metabolism, insulin sensitivity and suspected fatty liver in children. We measured body mass index (BMI), z-score BMI, caliper skinfold thickness, waist and hip circumference in 94 participants (mean age 9.7 +/-2.2 years). Fasting blood glucose, insulin, HOMA score, lipid profile and transaminases (ALT, AST) were measured. Fatty liver and skinfold thickness were evaluated by means of ultrasound. The z-score BMI was 2.01 +/-0.39 (mean +/- SD), and the duration of obesity was 4.3+/-3.03 years. A positive correlation was found between caliper and US skinfold thickness for tricipital (r= 0.33; p= 0.003) and sovrailiac skinfold (r= 0.34; p=0.003). Fatty liver was diagnosed in 64% of children and it was positively related to anthropometric measurements. The three sub-groups--group 0 (normal US liver and normal transaminases); group 1 (US fatty liver and normal transaminases); group 2 (US fatty liver and elevated transaminases)--showed a difference concerning z-score BMI, insulin and HOMA parameters (Tukey test: z score BMI group 1 vs group 0 and 2 vs group 0; serum insulin: group 2 vs group 1 and group 2 vs group 0; HOMA IR: group 2 vs group 1 and group 2 vs group 0). Moderately obese children with steatosis exhibited a clear increase of insulin and insulin resistance which represents indices of a future metabolic syndrome. In addition, it is important to perform a liver ultrasound since transaminases seems to be not adequate for the diagnosis of fatty liver.

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.

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).

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.

Human chorionic gonadotropin free beta-subunit in the human seminal plasma: a new marker for spermatogenesis?

UNLABELLED: In the past 20 years, several factors were detected in the human seminal plasma and proposed as markers for spermatogenesis. Human chorionic gonadotropin (hCG) and its beta-subunit were therefore investigated, and their seminal levels were found to be higher than those detected in the serum and to correlate with sperm parameters. OBJECTIVE: We designed a retrospective study to determine the suitability of hCG free beta-subunit concentration in the seminal plasma of fertile and infertile male patients as marker of spermatogenesis. STUDY DESIGN: A total of 79 infertile male patients were divided into four groups by their semen analysis results (group 1 [n=8]: azoospermia; group 2 [n=21]: severe oligozoospermia; group 3 [n=40]: oligoasthenospermia (OAS); group 4 [n=10]: asthenospermia) and 10 healthy volunteers of proven fertility were evaluated. RESULTS: The hCG free beta-subunit levels in the seminal plasma were found to be significantly higher (P<0.0001) in the control group in respect to those assayed in the infertile patients and showed a correlation with sperm count (r=0.5) and total motile sperm density (r=0.5). Twenty-five patients were on treatment with oral Mesterolone (100mg daily) plus Tamoxifen (20mg daily) for 3-6 months. Apart from a significant improvement (P<0.05) in sperm morphology, no significant changes in sperm count and motility were observed after the treatment in all the patients. In the seminal plasma of 10 patients who showed a significant increase in sperm count, hCG free beta-subunit levels were found to be significantly higher compared to those detected in the remaining patients (P<0.01). In all patients, these levels remained unchanged after the treatment. CONCLUSIONS: The evidence regarding the positive correlation between hCG free beta-subunit levels in the seminal plasma and sperm concentration is consistent with the previous results regarding hCG levels. A previous study demonstrated that testosterone levels in seminal plasma correlated with sperm concentrations; from the same evidence regarding hCG we hypothesize that seminal plasma testosterone and hCG levels are correlated. Thus, hCG may play a paracrine role in the intratesticular regulation of testosterone secretion.

Serum 90K/MAC-2BP glycoprotein in patients with liver cirrhosis and hepatocellular carcinoma: a comparison with alpha-fetoprotein.

Glycoprotein 90K/MAC-2BP is a member of the scavenger receptor cystein-rich protein superfamily, which is thought to be involved in immune surveillance, defending the body against pathogens and cancer. 90K serum levels are elevated in patients with cancer of various origins and in viral infections, such as human immunodeficiency virus and hepatitis C virus (HCV). Because in patients with HCV-related cirrhosis the incidence of hepatocellular carcinoma (HCC) is high, in the present paper we examined, by means of an enzyme-linked immunosorbent assay, the 90K serum levels in 103 patients with liver cirrhosis, and in 69 with HCC, and compared them to alpha-fetoprotein, the reference tumor marker for this neoplasm. Serum levels of 90K (cut-off 14 microg/ml) were elevated both in cirrhosis (39%) and HCC (46%) compared to controls (14.1 microg/ml vs. 10.6 microg/ml in cirrhosis, and 14.8 microg/ml vs. 9.1 microg/ml in HCC, p < or = 0.001). There was a significant association with the presence of anti-HCV antibodies. 90K was found to be a non-specific tumor marker which is complementary to alpha-fetoprotein on the basis of its probable different biological significance. In fact, 74% of HCC patients had at least one positive marker. Combined use of 90K and alpha-fetoprotein could improve the sensitivity of a single test in the diagnosis of HCC.

Insulin and gall stones: a population case control study in southern Italy.

BACKGROUND: Hyperinsulinaemia has been associated with many common diseases in developed countries, such as ischaemic heart disease and colon cancer. Gall stones are also very prevalent in these countries but little is known about the association between insulin and gall stones. AIMS: To study the relationships between insulin and the incidence of gall stones in a sample of the general population. SUBJECTS AND METHODS: Between May 1985 and June 1986, systematic sampling from the electoral register of Castellana, a small town in southern Italy, yielded 2472 subjects who had their gall bladder checked for gall stones by ultrasonography. Between May 1992 and June 1993, 1962 of the 2235 subjects without gall stones at the first examination agreed to a further ultrasound examination. A total of 101 subjects with newly diagnosed gall stones and 303 randomly chosen controls entered the study. Serum insulin was determined by radioimmunoassay, and concentrations of cholesterol, cholesterol high density lipoprotein (HDL), glucose, and triglycerides by standard enzymatic colorimetric methods. Unconditional multiple logistic regression was used to study the association between insulin and gall stones, controlling for the most common confounding factors. RESULTS: In individuals with no clinical diagnosis of diabetes and serum glucose <7 mmol/l, insulin was associated with gall stones. This association persisted even after controlling for sex, age, body mass index, and serum glucose. The risk of gall stones in the highest quintile of serum insulin was 2.66 (95% confidence interval 1.04-6.72; chi(2) test for trend, p=0.03). The association of insulin with gall stones persisted when total and HDL cholesterol were entered in the logistic regression models, and only slightly decreased when serum triglycerides were included in the model. CONCLUSIONS: The results of the study indicate that hyperinsulinaemia may play an important role in the aetiology of gall stones even in individuals without diabetes and with normal serum glucose levels.

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.