Background and aims: The genetic load in coeliac disease has hitherto been inferred from case series or anecdotally referred twin pairs. We have evaluated the genetic component in coeliac disease by ...estimating the concordance rate for the disease among twin pairs in a large population based study. Methods: The Italian Twin Registry was matched with the membership lists of a patient support group. Forty seven twin pairs were recruited and screened for antiendomysial (EMA) and antihuman-tissue transglutaminase (anti-tTG) antibodies; zygosity was verified by DNA fingerprinting and twins were typed for HLA class II DRB1 and DQB1 molecules. Results: Concordance rates for coeliac disease differ significantly between monozygotic (MZ) (0.86 probandwise and 0.75 pairwise) and dizygotic (DZ) (0.20 probandwise and 0.11 pairwise) twins. This is the highest concordance so far reported for a multifactorial disease. A logistic regression model, adjusted for age, sex, number of shared HLA haplotypes, and zygosity, showed that genotypes DQA1*0501/DQB1*0201 and DQA1*0301/DQB1*0302 (encoding for heterodimers DQ2 and DQ8, respectively) conferred to the non-index twin a risk of contracting the disease of 3.3 and 1.4, respectively. The risk of being concordant for coeliac disease estimated for the non-index twin of MZ pairs was 17 (95% confidence interval 2.1–134), independent of the DQ at risk genotype. Conclusion: This study provides substantial evidence for a very strong genetic component in coeliac disease, which is only partially due to the HLA region.
The pathogenesis of transposition of the great arteries (TGA) is still largely unknown. In general, TGA is not associated with the more common genetic disorders nor with extracardiac anomalies, ...whereas it can be found in individuals with lateralisation defects, heterotaxy and asplenia syndrome (right isomerism).
To analyse genes previously associated with heterotaxy in order to assess mutations in familial TGA unassociated with other features of laterality defects.
Probands of seven families with isolated TGA and a family history of concordant or discordant congenital heart disease were screened for mutations in the ZIC3, ACVR2B, LEFTYA, CFC1, NODAL, FOXH1, GDF1, CRELD1, GATA4 and NKX2.5 genes.
Mutation analysis allowed the identification of three sequence variations in two out of seven TGA probands. A FOXH1 (Pro21Ser) missense variant was found in a proband who was also heterozogous for an amino acid substitution (Gly17Cys) in the ZIC3 gene. This ZIC3 variant was also found in another family member with a second sequence variation (Val150Ile) in the NKX2.5 gene homeodomain who was affected by multiple ventricular septal defects. A second proband was found to harbour a splice site variant (IVS2-1G-->C) in the NODAL gene.
The present study provides evidence that some cases of familial TGA are caused by mutations in laterality genes and therefore are part of the same disease spectrum of heterotaxy syndrome, and argues for an oligogenic or complex mode of inheritance in these pedigrees.
Purpose of Review
Patients with hypertrophic cardiomyopathy (HCM) who have left ventricular outflow tract obstruction (LVOTO) often experience severe symptoms and functional limitation. Relief of ...LVOTO can be achieved by two invasive interventions, i.e., surgery myectomy and alcohol septal ablation (ASA), leading in experienced hands to a dramatic improvement in clinical status. Despite extensive research, however, the choice of the best option in individual patients remains challenging and poses numerous clinical dilemmas.
Recent Findings
Invasive strategies have been recently incorporated in recommendations for the diagnosis and treatment of HCM on both sides of the Atlantic. These guidelines are based on a bulk of well-designed but retrospective studies as well as on expert opinions. Evidence now exists that adequate evaluation and management of HCM requires a multidisciplinary team capable of choosing the best available options.
Summary
Management of LVOTO still varies largely based on local expertise and patient preference. Following the trend that has emerged for other cardiac diseases amenable to invasive interventions, the concept of a “HCM heart team” is coming of age.
Recent evidence supports the concept that progression of chronic heart failure (CHF) depends upon an imbalance of catabolic forces over the anabolic drive. In this regard, multiple hormonal ...deficiency syndrome (MHDS) significantly has impacts upon CHF progression, and is associated with a worse clinical status and increased mortality. The T.O.S.CA. (Trattamento Ormonale nello Scompenso CArdiaco; Hormone Therapy in Heart Failure) Registry (clinicaltrial.gov = NCT02335801) tests the hypothesis that anabolic deficiencies reduce survival in a large population of mild-to-moderate CHF patients. The T.O.S.CA. Registry is a prospective multicenter observational study coordinated by “Federico II” University of Naples, and involves 19 centers situated throughout Italy. Thyroid hormones, insulin-like growth factor-1, total testosterone, dehydroepiandrosterone , and insulin are measured at baseline and every year for a patient-average follow-up of 3 years. Subjects with CHF are divided into two groups: patients with one or no anabolic deficiency, and patients with two or more anabolic deficiencies at baseline. The primary endpoint is the composite of all-cause mortality and cardiovascular hospitalization. Secondary endpoints include the composite of all-cause mortality and hospitalization, the composite of cardiovascular mortality and cardiovascular hospitalization, and change of
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peak. Patient enrollment started in April 2013, and was completed in July 2017. Demographics and main clinical characteristics of enrolled patients are provided in this article. Detailed cross-sectional results will be available in late 2018. The T.O.S.CA. Registry represents the most robust prospective observational trial on MHDS in the field of CHF. The study findings will advance our knowledge with regard to the intimate mechanisms of CHF progression and hopefully pave the way for future randomized clinical trials of single or multiple hormonal replacement therapies in CHF.
The prevalence of obesity is increasing among children in the developed world. The association of obesity and abnormal cardiac function is still debated. The reported changes may reflect the role of ...comorbidities that contribute to ventricular dysfunction. Obese children, without arterial hypertension, may be a unique clinical opportunity to evaluate the effect of obesity, per se, on myocardial function, excluding the influence of possible comorbidities. We sought to define the preclinical effects of obesity on the cardiovascular system, of healthy children with excess weight who have no other clinically appreciable cause of heart disease, using the more sensitive ultrasonic-derived strain and strain rate (SR) imaging.
We studied 300 subjects divided into two groups: (i) obese children (Group O: n=150; age, 12+/-3 years); (ii) healthy lean children comparable for age, sex, and pubertal stage (Referents: n=150; mean age, 12+/-3 years). Systolic (SBP) and diastolic blood pressure (DBP), as well as 24 h-SBP and 24 h-DBP were comparable between groups. Left ventricular (LV) mass/height(2.7) was increased (P<0.0001) in Group O (46+/-12 g/m(2.7)) when compared with Referents (31+/-14 gm(2.7)). Standard echocardiographic indices of global systolic function were similar in the two groups. Intima-media thickness measured at the common carotid artery was not significantly different (P=0.4) in obese children (0.46+/-0.09 mm) when compared with Referents (0.45+/-0.07 mm). Obese children showed regional longitudinal peak systolic myocardial deformation properties (SR=-1.4+/-0.7 s(-1)) lower (P<0.0001) than those of Referents (SR=-2.2+/-0.5) in both left and right ventricle. In multivariable analysis, average peak systolic SR was significantly correlated with homeostasis model assessment of insulin resistance (P<0.01; coefficient, 0.02; SE, 0.011), and insulin serum concentration (P<0.01; coefficient, 0.05; SE, 0.023). Average LV peak systolic strain was significantly correlated with body mass index (P=0.0001; coefficient, 0.06; SE, 0.016), LVM/H(2.7) (P=0.006; coefficient, 0.016; SE, 0.018).
Our study demonstrated that obesity, in absence of hypertension, is associated with significant reduction in systolic myocardial deformation properties already in childhood involving both right and left ventricle. Obesity not only is a risk factor for later cardiovascular disease, but also is associated with contemporaneous and significant impairment of longitudinal myocardial deformation properties.
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