Coronary flow-reserve (CFR) can be impaired in non-ischaemic dilated cardiomyopathy (DCM), unmasking a coronary microcirculatory dysfunction of potential prognostic impact. The aim of the present ...study is to evaluate the prognostic value of Doppler echocardiographic-derived CFR in patients with DCM.
We evaluated 129 DCM patients (85 male; age 62+/-11) by transthoracic dipyridamole (0.84 mg/kg in 10 min) stress echocardiography. All patients had an ejection fraction<40% (mean 32+/-7) and angiographically normal coronary arteries with NYHA class<or=3. CFR was assessed on left anterior descending artery using pulsed Doppler as the ratio of maximal peak vasodilation (dipyridamole) to rest diastolic flow velocity. All patients were followed-up for a median of 22 months. Mean CFR was 2.0+/-0.5. At individual patient analysis 46 patients had normal (CFR>2.0) and 83 had abnormal CFR. During follow-up, 18 patients died and 33 showed worsening of NYHA class. The worse event-free survival was observed in those patients with an abnormal CFR when compared with those having a normal CFR at high dose of dipyridamole (70 vs. 22%, at 75 months of follow-up, P<0.0001). In the multivariable analysis, severity of mitral insufficiency (HR=1.9, 95% CI=1.06-2.87), abnormal CFR (HR=4.0, 95% CI=1.1-15.6), resting wall motion score index (HR=6.9, 95% CI=1.5-30.7) were independent predictors of survival.
In DCM patients, CFR is often impaired. A reduced CFR during vasodilator stress is an independent prognostic marker of bad prognosis.
Alkaptonuria (AKU) is a rare metabolic disorder caused by a deficient enzyme in the tyrosine degradation pathway, homogentisate 1,2-dioxygenase (HGD). In 172 AKU patients from 39 countries, we ...identified 28 novel variants of the HGD gene, which include three larger genomic deletions within this gene discovered via self-designed multiplex ligation-dependent probe amplification (MLPA) probes. In addition, using a reporter minigene assay, we provide evidence that three of eight tested variants potentially affecting splicing cause exon skipping or cryptic splice-site activation. Extensive bioinformatics analysis of novel missense variants, and of the entire HGD monomer, confirmed mCSM as an effective computational tool for evaluating possible enzyme inactivation mechanisms. For the first time for AKU, a genotype-phenotype correlation study was performed for the three most frequent HGD variants identified in the Suitability Of Nitisinone in Alkaptonuria 2 (SONIA2) study. We found a small but statistically significant difference in urinary homogentisic acid (HGA) excretion, corrected for dietary protein intake, between variants leading to 1% or >30% residual HGD activity. There was, interestingly, no difference in serum levels or absolute urinary excretion of HGA, or clinical symptoms, indicating that protein intake is more important than differences in HGD variants for the amounts of HGA that accumulate in the body of AKU patients.
MicroRNAs are able to modulate gene expression in a range of diseases. We focused on microRNAs as potential contributors to the pathogenesis of ascending aorta (AA) dilatation in patients with ...stenotic tricuspid (TAV) or bicuspid aortic valve (BAV). Aortic specimens were collected from the ‘concavity’ and the ‘convexity’ of mildly dilated AAs and of normal AAs from heart transplant donors. Aortic RNA was analyzed through PCR arrays, profiling the expression of 84 microRNAs involved in cardiovascular disease. An in silico analysis identified the potential microRNA–mRNA interactions and the enriched KEGG pathways potentially affected by microRNA changes in dilated AAs. Distinct signatures of differentially expressed microRNAs are evident in TAV and BAV patients vs. donors, as well as differences between aortic concavity and convexity in patients only. MicroRNA changes suggest a switch of SMC phenotype, with particular reference to TAV concavity. MicroRNA changes potentially affecting mechanotransduction pathways exhibit a higher prevalence in BAV convexity and in TAV concavity, with particular reference to TGF-β1, Hippo, and PI3K/Akt/FoxO pathways. Actin cytoskeleton emerges as potentially affected by microRNA changes in BAV convexity only. MicroRNAs could play distinct roles in BAV and TAV aortopathy, with possible implications in diagnosis and therapy.
Abstract
Aims
To obtain the normal ranges for echocardiographic measurements of left atrial (LA) function from a large group of healthy volunteers accounting for age and gender.
Methods and results
A ...total of 371 (median age 45 years) healthy subjects were enrolled at 22 collaborating institutions collaborating in the Normal Reference Ranges for Echocardiography (NORRE) study of the European Association of Cardiovascular Imaging (EACVI). Left atrial data sets were analysed with a vendor-independent software (VIS) package allowing homogeneous measurements irrespective of the echocardiographic equipment used to acquire data sets. The lowest expected values of LA function were 26.1%, 48.7%, and 41.4% for left atrial strain (LAS), 2D left atrial emptying fraction (LAEF), and 3D LAEF (reservoir function); 7.7%, 24.2%, and −0.53/s for LAS-active, LAEF-active, and LA strain rate during LA contraction (SRa) (pump function) and 12.0% and 21.6% for LAS-passive and LAEF-passive (conduit function). Left atrial reservoir and conduit function were decreased with age while pump function was increased. All indices of reservoir function and all LA strains had no difference in both gender and vendor. However, inter-vendor differences were observed in LA SRa despite the use of VIS.
Conclusion
The NORRE study provides contemporary, applicable echocardiographic reference ranges for LA function. Our data highlight the importance of age-specific reference values for LA functions.
Background: The consumption of high-fructose beverages is associated with higher risk for T2D. Fructose can stimulate GLP-1 secretion in lean adults, in the absence of any inhibitory effect on ...appetite. We hypothesized that the ingestion of glucose (GLC) and fructose (FRU) may differentially stimulate GLP-1 and insulin response in lean and obese adolescents.
Methods: We studied 14 lean (4F, 15.9±1.6y, 21.8±2.2 kg/m2) and 23 obese (5F, 15.1±1.6y, 34.5±4.6 kg/m2) adolescents. Participants received, in a double blinded cross-over study, 75g of GLC or FRU. Plasma was obtained every 10min for 60 minutes GLC was determined by YSI Analyzer; insulin and GLP-1 were measured by Millipore RIA; data were expressed as incremental values from baseline and compared by linear mixed effect model between lean and obese.
Results: Obese adolescents exhibited greater insulin (p<0.001) and GLP-1 (p<0.001) rise after FRU than lean peers, at each time points (Figure), in the absence of a significant difference in plasma GLC (p0.699). After GLC ingestion, neither the rise in plasma GLC (p0.099), nor in insulin (p0.099) and GLP-1(p0.083) differed between lean and obese youths.
Conclusion: Fructose, but not glucose, ingestion elicits higher insulin and GLP-1 response in obese as compared to lean adolescents. High-fructose consumption may contribute to the hyperinsulinemic phenotype through a GLP-1 mediated mechanism.
Disclosure
A. Galderisi: None. M.A. Van Name: Research Support; Self; Novo Nordisk Inc. C. Giannini: None. M. Savoye: None. S. Caprio: None.
Funding
National Institutes of Health (1R01DK085577-01, R01HD40787, R01HD28016; P30DK045735, K12DK094714-02; R01DK111038-01A1; Pediatric Endocrine Society; Robert E. Leet and Clara Guthrie Patterson Trust; European Medical International Framework (EMIF115372)
Background: Hyperinsulinemia results from β-cell ompensatory adaptation to insulin resistance and reduced insulin clearance. We examined the relationship between hepatic/peripheral insulin clearance ...and β-cell function in lean and obese insulin sensitive (IS) and insulin resistant (IR) adolescents.
Methods: A 2-step euglycemic hyperinsulinemic clamp and an hyperglycemic clamp were performed in 153 youths (73F, 14.4±3.3y) to evaluate hepatic (MCR1) and peripheral (MCR2) insulin clearance, β-cell function (DIcpep) and insulin sensitivity. Participants were grouped as:non-Obese NGT (nOb-NGT, n=23), obese NGT-IS (Ob-NGT-IS, n=47), obese NGT-IR (Ob-NGT-IR, n=47), and obese IGT (Ob-IGT, n=36). IS and IR were defined according to the median M (glucose disposal) from euglycemic clamp. Effect of MCR1-2, sex, age, BMI, Tanner stage, fasting/2h-glucose, ethnicity on DIcpepwas estimated by multivariate regression model.
Results: IS, MCR1/MCR2 did not differ between nOb-NGT and Ob-NGT-IS. MCR1 was lower in Ob-NGT-IR and Ob-IGT than nOb-NGT, while MCR2 only declined in the Ob-IGT. (upper panels) MCR1 and MCR2 were the sole determinants of DIcpep (p0.006 and p0.015), as confirmed by ~50% reduction in DIcpep of the lowest tertiles of MCR1 and MCR2. (lower panels).
Conclusion: In obese adolescents, lower MCR1 and MCR2 are independently associated with a blunted β-cell function thus playing a key role in youth onset T2D.
Disclosure
A. Galderisi: None. D. Trico: None. C. Giannini: None. N. Santoro: None. S. Caprio: None. R. Weiss: Consultant; Self; Medtronic MiniMed, Inc.
Funding
National Institutes of Health (R01DK085577-01, R01HD40787, R01HD28016, P30DK045735, K12DK094714-02, R01DK111038-01A1); Robert E. Leet and Clara Guthrie Patterson Trust; European Medical International Framework (EMIF115372)
Background: Hyperinsulinemia results from β-cell ompensatory adaptation to insulin resistance and reduced insulin clearance. We examined the relationship between hepatic/peripheral insulin clearance ...and β-cell function in lean and obese insulin sensitive (IS) and insulin resistant (IR) adolescents. Methods: A 2-step euglycemic hyperinsulinemic clamp and an hyperglycemic clamp were performed in 153 youths (73F, 14.4±3.3y) to evaluate hepatic (MCR1) and peripheral (MCR2) insulin clearance, β-cell function (DIcpep) and insulin sensitivity. Participants were grouped as:non-Obese NGT (nOb-NGT, n=23), obese NGT-IS (Ob-NGT-IS, n=47), obese NGT-IR (Ob-NGT-IR, n=47), and obese IGT (Ob-IGT, n=36). IS and IR were defined according to the median M (glucose disposal) from euglycemic clamp. Effect of MCR1-2, sex, age, BMI, Tanner stage, fasting/2h-glucose, ethnicity on DIcpep was estimated by multivariate regression model. Results: IS, MCR1/MCR2 did not differ between nOb-NGT and Ob-NGT-IS. MCR1 was lower in Ob-NGT-IR and Ob-IGT than nOb-NGT, while MCR2 only declined in the Ob-IGT. (upper panels) MCR1 and MCR2 were the sole determinants of DIcpep (p0.006 and p0.015), as confirmed by ~50% reduction in DIcpep of the lowest tertiles of MCR1 and MCR2. (lower panels). Conclusion: In obese adolescents, lower MCR1 and MCR2 are independently associated with a blunted β-cell function thus playing a key role in youth onset T2D.
Right ventricular (RV) systolic function has a critical role in determining the clinical outcome and the success of using left ventricular assist devices (LVADs) in patients with refractory heart ...failure. RV deformation analysis by speckle tracking echocardiography (STE) has recently allowed a deeper analysis of RV longitudinal function. The aim of the study was to observe RV function by STE in patients with advanced heart failure before and after LVAD implantation.
Transthoracic echo Doppler was performed in 10 patients referred for LVAD therapy at baseline and with serial echocardiograms after LVAD implantation. In a sub-group of 4 patients, an echocardiographic evaluation was also made after intra-aortic balloon pump (IABP) support was initiated and before LVAD implantation. All echocardiographic images were analyzed off-line to calculate the free wall RV longitudinal strain (RVLS).
Three patients who presented the lowest free wall RVLS values at baseline, showed a progressive decline of RVLS after LVAD implant, presenting finally RV failure; however, patients with higher values of RVLS at baseline presented a further and overt increase of strain values in the course of follow-up. The overall performance for the prediction of RV failure after LVAD implant was greatest for free wall RVLS (area under the curve, 0.93). For the sub-group receiving the IABP as an intermediate step, only 2 patients with an increase of RVLS after IABP implantation also showed an increase of RVLS levels, after subsequent LVAD implantation. The 2 patients without an increase of RVLS after IABP implantation also presented with RV failure after LVAD therapy.
This study of 10 patients indicates that the new parameter of RVLS, representing RV myocardial deformation, may have important clinical implications for the selection and management of LVAD patients. A large multicenter study is required to confirm these observations and to quantify the clinical significance of changes in RVLS value.
The cells present in the stromal compartment of many tissues are a heterogeneous population containing stem cells, progenitor cells, fibroblasts, and other stromal cells. A SSEA3(+) cell ...subpopulation isolated from human stromal compartments showed stem cell properties. These cells, known as multilineage-differentiating stress-enduring (MUSE) cells, are capable of resisting stress and possess an excellent ability to repair DNA damage. We isolated MUSE cells from different mouse stromal compartments, such as those present in bone marrow, subcutaneous white adipose tissue, and ear connective tissue. These cells showed overlapping in vitro biological properties. The mouse MUSE cells were positive for stemness markers such as SOX2, OCT3/4, and NANOG. They also expressed TERT, the catalytic telomerase subunit. The mouse MUSE cells showed spontaneous commitment to differentiation in meso/ecto/endodermal derivatives. The demonstration that multilineage stem cells can be isolated from an animal model, such as the mouse, could offer a valid alternative to the use of other stem cells for disease studies and envisage of cellular therapies.
In this study we assessed the contribution of psychopathology, including the two domains of negative symptoms (motivational deficit and expressive deficit), processing speed as an index of ...neurocognition, and emotion recognition, as an index of social cognition, to poor functional outcomes in people with schizophrenia.
The Positive and Negative Syndrome Scale was used to evaluate positive symptoms and disorganization and the Brief Negative Symptom Scale to assess negative symptoms. The Symbol Coding and the Trail Making Test A and B were used to rate processing speed and the Facial Emotion Identification Test to assess emotion recognition. Functional outcome was assessed with the Personal and Social Performance Scale (PSP). Regression analyses were performed to identify predictors of functional outcome. Mediation analyses was used to investigate whether social cognition and negative symptom domains fully or partially mediated the impact of processing speed on functional outcome.
One hundred and fifty subjects from 8 different European centers were recruited. Our data showed that the expressive deficit predicted global functioning and together with motivational deficit fully mediated the effects of neurocognition on it. Motivational deficit was a predictor of personal and social functioning and fully mediated neurocognitive impairment effects on the same outcome. Both motivational deficit and neurocognitive impairment predicted socially useful activities, and the emotion recognition domain of social cognition partially mediated the impact of neurocognitive deficits on this outcome.
Our results indicate that pathways to functional outcomes are specific for different domains of real-life functioning and that negative symptoms and social cognition mediate the impact of neurocognitive deficits on different domains of functioning. Our results suggest that both negative symptoms and social cognition should be targeted by psychosocial interventions to enhance the functional impact of neurocognitive remediation.
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