Impaired Relaxation and Reduced Lusitropic Reserve in Atrial Myocardium in the Obese Patients

Background: Obesity can influence the structure and function of the atrium, but most studies focused on the relationship of body mass index (BMI) and overt left atrium (LA) dysfunction as assessed by clinical imaging. We combined the assessment of right atrium (RA) function in vivo and in vitro in obese and non-obese patients scheduled for elective cardiac surgery. Methods: Atrial structure and function were quantified pre-operatively by echocardiography. RA tissue removed for the establishment of extracorporeal support was collected and RA trabeculae function was quantified in vitro at baseline and with adrenergic stimulation (isoproterenol). Fatty acid-binding protein 3 (FABP3) was quantified in RA tissue. Results were stratified according to the BMI of the patients. Results: About 76 patients were included pre-operatively for the echocardiographic analysis. RA trabeculae function at baseline was finally quantified from 46 patients and RA function in 28 patients was also assessed with isoproterenol. There was no significant correlation between BMI and the parameters of atrial function measured by the clinical echocardiography. However, in vitro measurements revealed a significant correlation between BMI and a prolonged relaxation of the atrial myocardium at baseline, which persisted after controlling for the atrial fibrillation and diabetes by the partial correlation analysis. Acceleration of relaxation with isoproterenol was significantly lower in the obese group (BMI ≥ 30 kg/m(2)). As a result, relaxation with adrenergic stimulation in the obese group remained significantly higher compared to the overweight group (25 kg/m(2) ≤ BMI < 30 kg/m(2), p = 0.027) and normal group (18.5 kg/m(2) ≤ BMI < 25 kg/m(2), p = 0.036). There were no differences on impacts of the isoproterenol on (systolic) developed force between groups. The expression of FABP3 in the obese group was significantly higher compared to the normal group (p = 0.049) and the correlation analysis showed the significant correlations between the level of FABP3 in the RA trabeculae function. Conclusion: A higher BMI is associated with the early subclinical changes of RA myocardial function with the slowed relaxation and reduced adrenergic lusitropy

Lung-to-Heart Nano-in-Micro Peptide Promotes Cardiac Recovery in a Pig Model of Chronic Heart Failure

Background: The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking. Objectives: In this study, the authors sought to assess tolerability and efficacy of an inhalable lung-to-heart nano-in-micro technology (LungToHeartNIM) for cardiac-specific targeting of a mimetic peptide (MP), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF. Methods: Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachypacing over 6&nbsp;weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% ± 8%), animals were randomized and treatment was started after 4&nbsp;weeks of tachypacing. HFrEF animals inhaled either a dry powder composed of mannitol-based microparticles embedding biocompatible MP-loaded calcium phosphate nanoparticles (dpCaP-MP) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment. Results: DpCaP-MP inhalation restored systolic function, as shown by an absolute LVEF increase over the treatment period of 17% ± 6%, while reversing cardiac remodeling and reducing pulmonary congestion. The effect was recapitulated ex&nbsp;vivo in cardiac myofibrils from treated HF animals. The treatment was well tolerated, and no adverse events occurred. Conclusions: The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeutic&nbsp;peptide to the diseased heart

Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene

Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the &#39;common disease, rare allele&#39; hypothesis

Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not