Prognostic and therapeutic implications of low aortic valve calcium score in patients with low gradient aortic stenosis.

INTRODUCTION: Low gradient (LG) aortic stenosis (AS) poses a diagnostic challenge. Aortic valve calcium score (AVCS) assessment has emerged as a complementary diagnostic method when echocardiography provides discordant results. However, the diagnostic and prognostic value of AVCS in LGAS has not been thoroughly studied. Our aims were to investigate the prognostic importance of AVCS in LGAS and to assess whether symptomatic patients with LGAS and low AVCS may benefit from aortic valve intervention (AVI). METHODS: 327 symptomatic patients (78.5±7.3 years, 51% women) with severe AS defined by the aortic valve area who underwent computed tomography for transcatheter aortic valve intervention (TAVI) planning were enrolled. AVCS was measured. AVCS<2000 AU in men and<1200 AU in women was considered low AVCS. RESULTS: 243 patients had high gradient (HG) and 84 had LGAS. Low AVCS was present in 25(10%) of the HG and 34(40%) of the LGAS cases. Over a median follow-up period of 4.9 years, 194 deaths occurred. In multivariate analysis, AVCS was a significant independent predictor of all-cause mortality among HGAS (aHR:2.317; CI:1.104-4.861; p= 0.026), but not among LGAS (aHR:0.848; CI:0.434-1.658; p=0.630) patients. After propensity score matching between patients who underwent AVI and those who were medically treated, AVI (94% TAVI) was a significant and independent predictor of survival among LG AS patients with low AVCS even after adjustment for clinical variables (aHR:0.102, CI:0.028-0.369; p<0.001). CONCLUSION: The prevalence of low AVCS is much higher in LGAS than in HGAS. In symptomatic severe LGAS low AVCS did not entail a better prognosis. AVI is equally beneficial in LGAS patients with high or low AVCS, similarly to HGAS.

Assessing genetic and environmental influences on epicardial and abdominal adipose tissue quantities: a classical twin study.

BACKGROUND/OBJECTIVES: Various adipose tissue compartments play an important role in the development of cardiometabolic diseases. The quantity of different fat compartments is influenced by genetic and environmental factors. The aim of our study was to evaluate the magnitude of genetic and environmental effects on epicardial, subcutaneous and visceral adipose tissue (EAT, SAT and VAT) quantities in a cohort of adult twin pairs. SUBJECTS/METHODS: In this cross-sectional study we investigated adult twins (57 monozygotic (MZ) and 33 dizygotic (DZ) same-gender twin pairs; 180 twin subjects). We measured EAT volume using electrocardiogram-gated native computed tomography (CT) scan of the heart, and abdominal SAT and VAT areas were quantified between the third and fourth lumbar vertebra on native CT images. We calculated genetic and environmental impact on the size of various adipose tissue compartments by analyzing co-twin correlations in MZ and DZ pairs separately, and furthermore by using genetic structural equation models. RESULTS: In co-twin analysis, MZ twins had stronger correlations than DZ twins for EAT (rMZ=0.81, rDZ=0.32), similar to SAT and VAT quantities (rMZ=0.80, rDZ=0.68 and rMZ=0.79, rDZ=0.48, respectively). In multi-trait model fitting analysis, the overall contribution of genetic factors to EAT, SAT and VAT volumes were 80%, 78% and 70%, whereas environmental factors were 20%, 22% and 30%, respectively. Common pathway model analyses indicated that none of the EAT, SAT and VAT phenotypes was independent of the other two. CONCLUSIONS: Genetic factors have substantial influence, while environmental factors have only a modest impact on EAT volume, abdominal SAT and VAT quantities. There is a considerable amount of common genetic background influencing the quantities of all three adipose tissue compartments.

Effects of genetic vs. environmental factors on cardiovascular autonomic function: a twin study.

AIMS: Cardiovascular autonomic function is often assessed in patients with diabetes by measuring heart rate variability and baroreflex sensitivity, the heritability of which is not fully understood. The present study was aimed to determine the effects of genetic and environmental factors on heart rate variability and baroreflex sensitivity in monozygotic and dizygotic adult healthy twin pairs. METHODS: A total of 101 (63 monozygotic, 38 dizygotic) adult twin pairs (n = 202; mean age 44.3 years) were investigated. Anthropometric variables and serum metabolic markers were measured, while environmental characteristics were evaluated by questionnaires. Linear and spectral indices of heart rate variability and baroreflex sensitivity were determined by non-invasive methods. All measurements were adjusted for age and gender (model 1) and for all significantly relevant covariates (model 2). Heritability A-C-E structural equation models were used for characterizing the proportion of additive genetic, shared and unshared environmental influences. RESULTS: Genetic influence of different cardiovascular autonomic indices was estimated between 10.3 and 39.4%, common environmental influence was found between 0.0 and 33.2%, while unshared environmental influence was observed between 60.6 and 81.4% in model 1 analysis. In multivariable-adjusted heritability estimates (model 2), the magnitude of the genetic effects decreased to 0.0%, common environmental influence was nearly unchanged (values between 4.4 and 14.5%), while unshared environmental influence slightly increased (values between 85.5 and 96.5%). CONCLUSIONS: Unshared environmental but not genetic factors have substantial influence on cardiovascular autonomic function, suggesting that appropriate treatment of all modifiable environmental factors is of importance in order to prevent or ameliorate cardiovascular autonomic neuropathy.

Rat neonatal beta cells lack the specialised metabolic phenotype of mature beta cells.

AIMS/HYPOTHESIS: Fetal and neonatal beta cells have poor glucose-induced insulin secretion and only gain robust glucose responsiveness several weeks after birth. We hypothesise that this unresponsiveness is due to a generalised immaturity of the metabolic pathways normally found in beta cells rather than to a specific defect. METHODS: Using laser-capture microdissection we excised beta cell-enriched cores of pancreatic islets from day 1 (P1) neonatal and young adult Sprague-Dawley rats in order to compare their gene-expression profiles using Affymetrix U34A microarrays (neonatal, n = 4; adult, n = 3). RESULTS: Using dChip software for analysis, 217 probe sets for genes/38 expressed sequence tags (ESTs) were significantly higher and 345 probe sets for genes/33 ESTs significantly lower in beta cell-enriched cores of neonatal islets compared with those of adult islets. Among the genes lower in the neonatal beta cells were key metabolic genes including mitochondrial shuttles (malate dehydrogenase, glycerol-3-phosphate dehydrogenase and glutamate oxalacetate transaminase), pyruvate carboxylase and carnitine palmitoyl transferase 2. Differential expression of these enzyme genes was confirmed by quantitative PCR on RNA from isolated neonatal (P2 until P28) and adult islets and with immunostaining of pancreas. Even by 28 days of age some of these genes were still expressed at lower levels than in adults. CONCLUSIONS/INTERPRETATION: The lack of glucose responsiveness in neonatal islets is likely to be due to a generalised immaturity of the metabolic specialisation of pancreatic beta cells.

Mafa expression enhances glucose-responsive insulin secretion in neonatal rat beta cells.

AIM/HYPOTHESIS: Neonatal beta cells lack glucose-stimulated insulin secretion and are thus functionally immature. We hypothesised that this lack of glucose responsiveness results from a generalised low expression of genes characteristic of mature functional beta cells. Important glucose-responsive transcription factors, Mafa and Pdx1, regulate genes involved in insulin synthesis and secretion, and have been implicated in late beta cell development. The aim of this study was to assess whether Mafa and/or Pdx1 regulates the postnatal functional maturation of beta cells. METHODS: By quantitative PCR we evaluated expression of these and other beta cell genes over the first month compared with adult. After infection with adenovirus expressing MAFA, Pdx1 or green fluorescent protein (Gfp), P2 rat islets were evaluated by RT-PCR and insulin secretion with static incubation and reverse haemolytic plaque assay (RHPA). RESULTS: At P2 most beta cell genes were expressed at about 10% of adult, but by P7 Pdx1 and Neurod1 no longer differ from adult; by contrast, Mafa expression remained significantly lower than adult through P21. Overexpression of Pdx1 increased Mafa, Neurod1, glucokinase (Gck) mRNA and insulin content but failed to enhance glucose responsiveness. Similar overexpression of MAFA resulted in increased Neurod1, Nkx6-1, Gck and Glp1r mRNAs and no change in insulin content but, importantly, acquisition of glucose-responsive insulin secretion. Both the percentage of secreting beta cells and the amount of insulin secreted per beta cell increased, approaching that of adult beta cells. CONCLUSIONS/INTERPRETATION: In the process of functional maturation acquiring glucose-responsive insulin secretion, neonatal beta cells undergo a coordinated gene expression programme in which Mafa plays a crucial role.

The interferon-induced helicase IFIH1 Ala946Thr polymorphism is associated with type 1 diabetes in both the high-incidence Finnish and the medium-incidence Hungarian populations.

AIMS/HYPOTHESIS: The rs1990760 polymorphism (Ala946Thr) of interferon induced with helicase C domain 1 (IFIH1) has been proposed to associate with type 1 diabetes. In this study, association between IFIH1 Ala946Thr and type 1 diabetes was investigated in two distinct white populations, the Hungarians and Finns. METHODS: The rs1990760 polymorphism was genotyped in 757/509 Hungarian/Finnish childhood-onset cases, 499/250 Hungarian/Finnish control individuals and in 529/924 Hungarian/Finnish nuclear family trios. Disease association was tested using case-control and family-based approaches. A meta-analysis of data from 9,546 cases and 11,000 controls was also performed. RESULTS: In the Hungarian dataset, the A allele was significantly more frequent among cases than among controls (OR 1.29, 95% CI 1.10-1.52; p = 0.002). Combined analysis of Hungarian and Finnish datasets revealed a strong disease association (OR 1.235, 95% CI 1.083-1.408; p = 0.002). Furthermore, the A allele was significantly overtransmitted in both family trio datasets (p = 0.017 in Hungarians; p = 0.007 in Finns). The A allele was increased in Hungarian vs Finnish cases (64.9% vs 60.8% in Finns; p = 0.003). The meta-analysis yielded a significant effect for IFIH1 rs1990760 A allele on type 1 diabetes risk (OR 1.176, 95% CI 1.130-1.225; p = 5.3 x 10(-15)) with significant heterogeneity between effect sizes across the studied populations (p = 0.023). CONCLUSIONS/INTERPRETATION: This study represents the first independent confirmation of the association between type 1 diabetes and the IFIH1 gene in Hungarian and Finnish populations. Summarising the data published so far, a clear association between the Ala946Thr polymorphism and type 1 diabetes was detected, with an apparent difference in the contribution to disease susceptibility in different populations of European ancestry.