The cardiomyopathy of cystic fibrosis: a modern form of Keshan disease.

Introduction: We conducted a study to determine the prevalence of structural heart disease in patients with CF, the characteristics of a cardiomyopathy not previously described in this population, and its possible relationship with nutritional deficiencies in CF. Methods: We studied 3 CMP CF patients referred for heart-lung transplantation and a prospective series of 120 adult CF patients. All patients underwent a clinical examination, blood tests including levels of vitamins and trace elements, and echocardiography with evaluation of myocardial strain. Cardiac magnetic resonance imaging (CMR) was performed in patients with CMP and in a control group. Histopathological study was performed on hearts obtained in transplant or necropsy. Results: We found a prevalence of 10% (CI 4.6%-15.4%) of left ventricular (LV) dysfunction in the prospective cohort. Myocardial strain parameters were already altered in CF patients with otherwise normal hearts. Histopathological examination of 4 hearts from CF CMP patients showed a unique histological pattern of multifocal myocardial fibrosis similar to Keshan disease. Four of the five CF CMP patients undergoing CMR showed late gadolinium uptake, with a characteristic patchy pattern in 3 cases (p < 0.001 vs. CF controls). Selenium deficiency (Se < 60 µg/L) was associated with more severe LV dysfunction, higher prevalence of CF CMP, higher NTproBNP levels, and more severe pulmonary and digestive involvement. Conclusion: 10% of adults with CF showed significant cardiac involvement, with histological and imaging features resembling Keshan disease. Selenium deficiency was associated with the presence and severity of LV dysfunction in these patients.

Nanomechanical Phenotypes in Cardiac Myosin-Binding Protein C Mutants That Cause Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a disease of the myocardium caused by mutations in sarcomeric proteins with mechanical roles, such as the molecular motor myosin. Around half of the HCM-causing genetic variants target contraction modulator cardiac myosin-binding protein C (cMyBP-C), although the underlying pathogenic mechanisms remain unclear since many of these mutations cause no alterations in protein structure and stability. As an alternative pathomechanism, here we have examined whether pathogenic mutations perturb the nanomechanics of cMyBP-C, which would compromise its modulatory mechanical tethers across sliding actomyosin filaments. Using single-molecule atomic force spectroscopy, we have quantified mechanical folding and unfolding transitions in cMyBP-C domains targeted by HCM mutations that do not induce RNA splicing alterations or protein thermodynamic destabilization. Our results show that domains containing mutation R495W are mechanically weaker than wild-type at forces below 40 pN and that R502Q mutant domains fold faster than wild-type. None of these alterations are found in control, nonpathogenic variants, suggesting that nanomechanical phenotypes induced by pathogenic cMyBP-C mutations contribute to HCM development. We propose that mutation-induced nanomechanical alterations may be common in mechanical proteins involved in human pathologies.

Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Variants in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C), are the leading cause of HCM. However, the pathogenicity status of hundreds of MYBPC3 variants found in patients remains unknown, as a consequence of our incomplete understanding of the pathomechanisms triggered by HCM-causing variants. Here, we examined 44 nontruncating MYBPC3 variants that we classified as HCM-linked or nonpathogenic according to cosegregation and population genetics criteria. We found that around half of the HCM-linked variants showed alterations in RNA splicing or protein stability, both of which can lead to cMyBP-C haploinsufficiency. These protein haploinsufficiency drivers associated with HCM pathogenicity with 100% and 94% specificity, respectively. Furthermore, we uncovered that 11% of nontruncating MYBPC3 variants currently classified as of uncertain significance in ClinVar induced one of these molecular phenotypes. Our strategy, which can be applied to other conditions induced by protein loss of function, supports the idea that cMyBP-C haploinsufficiency is a fundamental pathomechanism in HCM.

Kir6.2, the Pore-Forming Subunit of ATP-Sensitive K+ Channels, Is Overexpressed in Human Posttraumatic Brain Contusions.

Brain contusions (BCs) are one of the most frequent lesions in patients with moderate and severe traumatic brain injury (TBI). BCs increase their volume due to peri-lesional edema formation and/or hemorrhagic transformation. This may have deleterious consequences and its mechanisms are still poorly understood. We previously identified de novo upregulation sulfonylurea receptor (SUR) 1, the regulatory subunit of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels and other channels, in human BCs. Our aim here was to study the expression of the pore-forming subunit of KATP, Kir6.2, in human BCs, and identify its localization in different cell types. Protein levels of Kir6.2 were detected by western blot (WB) from 33 contusion specimens obtained from 32 TBI patients aged 14-74 years. The evaluation of Kir6.2 expression in different cell types was performed by immunofluorescence in 29 contusion samples obtained from 28 patients with a median age of 42 years. Control samples were obtained from limited brain resections performed to access extra-axial skull base tumors or intraventricular lesions. Contusion specimens showed an increase of Kir6.2 expression in comparison with controls. Regarding cellular location of Kir6.2, there was no expression of this channel subunit in blood vessels, either in control samples or in contusions. The expression of Kir6.2 in neurons and microglia was also analyzed, but the observed differences were not statistically significant. However, a significant increase of Kir6.2 was found in glial fibrillary acidic protein (GFAP)-positive cells in contusion specimens. Our data suggest that further research on SUR1-regulated ionic channels may lead to a better understanding of key mechanisms involved in the pathogenesis of BCs, and may identify novel targeted therapeutic strategies.