Dystrophinopathy Phenotypes and Modifying Factors in Exon 45-55 Deletion

Duchenne muscular dystrophy (DMD) exon 45-55 deletion (del45-55) has been postulated as a model that could treat up to 60% of DMD patients, but the associated clinical variability and complications require clarification. We aimed to understand the phenotypes and potential modifying factors of this dystrophinopathy subset. This cross-sectional, multicenter cohort study applied clinical and functional evaluation. Next generation sequencing was employed to identify intronic breakpoints and their impact on the Dp140 promotor, intronic long noncoding RNA, and regulatory splicing sequences. DMD modifiers (SPP1, LTBP4, ACTN3) and concomitant mutations were also assessed. Haplotypes were built using DMD single nucleotide polymorphisms. Dystrophin expression was evaluated via immunostaining, Western blotting, reverse transcription polymerase chain reaction (PCR), and droplet digital PCR in 9 muscle biopsies. The series comprised 57 subjects (23 index) expressing Becker phenotype (28%), isolated cardiopathy (19%), and asymptomatic features (53%). Cognitive impairment occurred in 90% of children. Patients were classified according to 10 distinct index-case breakpoints; 4 of them were recurrent due to founder events. A specific breakpoint (D5) was associated with severity, but no significant effect was appreciated due to the changes in intronic sequences. All biopsies showed dystrophin expression of >67% and traces of alternative del45-57 transcript that were not deemed pathogenically relevant. Only the LTBP4 haplotype appeared associated the presence of cardiopathy among the explored extragenic factors. We confirmed that del45-55 segregates a high proportion of benign phenotypes, severe cases, and isolated cardiac and cognitive presentations. Although some influence of the intronic breakpoint position and the LTBP4 modifier may exist, the pathomechanisms responsible for the phenotypic variability remain largely unresolved. ANN NEUROL 2022;92:793-80

Use of a “CNI holidays” strategy in acute renal dysfunction late after heart transplant. Report of two cases

Background Acute renal dysfunction (ARD) may appear in heart transplant (HTx) patients both in the early postoperative period and during follow-up, even after several years. CD25 is a subunit of the interleukin-2 receptor which is found exclusively on activated CD4 T lymphocytes. CD25 is crucial for clonal expansion of anti-allograft host lymphocytes that mediate in acute rejection. There are experiences supporting the use of Anti-CD25 monoclonal antibodies (MAb) immediately after HTx in patients with ARD as a bridge to renal function recovery, allowing the temporary suspension of treatment with CNI. Methods In this study we report two cases of successful use of weekly MAb (basiliximab) in HTx patients who developed late ARD after HTx. Conclusions In coclusion, we think that in cases of ARD where CNI therapy plays a key role, the use of weekly doses of basiliximab allows CNI discontinuation until the restoration of renal function is achieved

Expression of B-type natriuretic peptide forms in ischemic human hearts

Background: This study sought to determine pro-B-type natriuretic peptide (proBNP), BNP, N-terminal proBNP (NT-proBNP) and GATA-4 in the same cardiac tissue, the correlation among them, and the influence of ischemic etiology on their levels. Methods: Protein levels were analyzed by Western blot techniques and mRNA expression was quantified by quantitative real-time polymerase chain reaction (RT-PCR) in a total of 33 human samples from ischemic (ICM), and control hearts. Results: Tissue protein level of proBNP is 1.5- and 12-fold higher than BNP or NT-proBNP respectively (p < 0.0001), and BNP protein level was 8-fold higher than that of NT-proBNP (p < 0.0001) in ICM hearts. Furthermore, proBNP mRNA expression was also increased in ICM (4-fold) compared to control hearts (p < 0.05), but there was not a significant increase in GATA-4 mRNA. Then, tissue NP forms showed a high correlation among them (proBNP vs. BNP r = 0.74, p < 0.0001; proBNP vs. NT-proBNP r = 0.43, p = 0.03; and BNP vs. NT-proBNP r = 0.61, p = 0.001, respectively). Furthermore, GATA-4 with proBNP (r = 0.536, p = 0.007) and BNP (r = 0.610, p = 0.001) in ischemic samples. Finally, we found that proBNP, BNP, NT-proBNP and GATA-4 were increased in our ICM hearts (by 14%, p = 0.004; 46%, p = 0.024, 33%, p = 0.002, and 49%, p = 0.026, respectively) compared with controls. Conclusions: This study shows higher protein level of proBNP in human hearts than of BNP and NT-proBNP, increased proBNP mRNA expression in ICM samples, and a good correlation among tissue natriuretic peptide and GATA-4. Finally, ICM shows a high tissue protein level of proBNP, BNP, NT-proBNP and GATA-4. © 2011 Elsevier Ireland Ltd. All rights reserved.The work was supported by the National Institute of Health Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III, [REDIN-SCOR 06/0003/1001, Project PI07/0462]; and Escuela Valenciana de Estudios para la Salud, [EVES AP039/2007], Spain.Cortes, R.; Rosello-Lleti, E.; Rivera, M.; Martinez-Dolz, L.; Salvador, A.; Sirera Pérez, R.; Portoles, M. (2012). Expression of B-type natriuretic peptide forms in ischemic human hearts. International Journal of Cardiology. 158(2):199-204. https://doi.org/10.1016/j.ijcard.2011.01.014S199204158

Repeated CMV Infection in a Heart Transplantation Patient

Infections are one of the leading causes of morbidity and mortality in heart transplantation (HTx). Cytomegalovirus (CMV) is the most common viral infection during the first year after HTx, but it is more unusual after this time. We present the case of a patient who underwent an HTx due to a severe ischemic heart disease. Although the patient did not have a high risk for CMV, infection, he suffered a reactivation during the first year and then up to six more episodes, especially in his eyes. The patient received different treatments against CMV and the immunosuppression was changed several times. Finally, everolimus was introduced instead of cyclosporine, and mycophenolate mofetil was withdrawn. The presented case provides an example of how the immunosupresion plays a key role in some infections in spite of being a suitable antiviral treatment

Novel Fibrillar and Non-Fibrillar Collagens Involved in Fibrotic Scar Formation after Myocardial Infarction

Following myocardial infarction (MI), adverse remodeling depends on the proper formation of fibrotic scars, composed of type I and III collagen. Our objective was to pinpoint the participation of previously unreported collagens in post-infarction cardiac fibrosis. Gene (qRT-PCR) and protein (immunohistochemistry followed by morphometric analysis) expression of fibrillar (types II and XI) and non-fibrillar (types VIII and XII) collagens were determined in RNA-sequencing data from 92 mice undergoing myocardial ischemia; mice submitted to permanent (non-reperfused MI, n = 8) or transient (reperfused MI, n = 8) coronary occlusion; and eight autopsies from chronic MI patients. In the RNA-sequencing analysis of mice undergoing myocardial ischemia, increased transcriptomic expression of collagen types II, VIII, XI, and XII was reported within the first week, a tendency that persisted 21 days afterwards. In reperfused and non-reperfused experimental MI models, their gene expression was heightened 21 days post-MI induction and positively correlated with infarct size. In chronic MI patients, immunohistochemistry analysis demonstrated their presence in fibrotic scars. Functional analysis indicated that these subunits probably confer tensile strength and ensure the cohesion of interstitial components. Our data reveal that novel collagens are present in the infarcted myocardium. These data could lay the groundwork for unraveling post-MI fibrotic scar composition, which could ultimately influence patient survivorship

Benefit of primary percutaneous coronary interventions in the elderly with ST segment elevation myocardial infarction

Objective: Primary percutaneous coronary intervention (P-PCI) has demonstrated its efficacy in patients with ST segment elevation myocardial infarction (STEMI). However, patients with STEMI ≥75 years receive less P-PCI than younger patients despite their higher in-hospital morbimortality. The objective of this analysis was to determine the effectiveness of P-PCI in patients with STEMI ≥75 years. Methods: We included 979 patients with STEMI ≥75 years, from the ATención HOspitalaria del Síndrome coronario study, a registry of 8142 consecutive patients with acute coronary syndrome admitted at 31 Spanish hospitals in 2014-2016. We calculated a propensity score (PS) for the indication of P-PCI. Patients that received or not P-PCI were matched by PS. Using logistic regression, we compared the effectiveness of performing P-PCI versus non-performance for the composite primary event, which included death, reinfarction, acute pulmonary oedema or cardiogenic shock during hospitalisation. Results: Of the included patients, 81.5 % received P-PCI. The matching provided two groups of 169 patients with and without P-PCI. Compared with its non-performance, P-PCI presented a composite event OR adjusted by PS of 0.55 (95% CI 0.34 to 0.89). Conclusions: Receiving a P-PCI was significantly associated with a reduced risk of major intrahospital complications in patients with STEMI aged 75 years or older

Benefit of primary percutaneous coronary interventions in the elderly with ST segment elevation myocardial infarction

Altres ajuts: Supported by: MARATO TV3 (081630); Red RedIAPP RD06/0018; CP12/03287; CIBER Epidemiología y Salud Pública; CIBERCV de enfermedades Cardiovasculares, Fondo Europeo de Desarrollo Regional (FEDER) (European Regional Development Funds -ERDF-); FIS CP12/03287, FIS 14/00449, FIS PI081327, FIS INTRASALUD PI1101801.Primary percutaneous coronary intervention (P-PCI) has demonstrated its efficacy in patients with ST segment elevation myocardial infarction (STEMI). However, patients with STEMI ≥75 years receive less P-PCI than younger patients despite their higher in-hospital morbimortality. The objective of this analysis was to determine the effectiveness of P-PCI in patients with STEMI ≥75 years. We included 979 patients with STEMI ≥75 years, from the ATención HOspitalaria del Síndrome coronario study, a registry of 8142 consecutive patients with acute coronary syndrome admitted at 31 Spanish hospitals in 2014-2016. We calculated a propensity score (PS) for the indication of P-PCI. Patients that received or not P-PCI were matched by PS. Using logistic regression, we compared the effectiveness of performing P-PCI versus non-performance for the composite primary event, which included death, reinfarction, acute pulmonary oedema or cardiogenic shock during hospitalisation. Of the included patients, 81.5 % received P-PCI. The matching provided two groups of 169 patients with and without P-PCI. Compared with its non-performance, P-PCI presented a composite event OR adjusted by PS of 0.55 (95% CI 0.34 to 0.89). Receiving a P-PCI was significantly associated with a reduced risk of major intrahospital complications in patients with STEMI aged 75 years or older

Comparison of 1-year outcome in patients with severe aorta stenosis treated conservatively or by aortic valve replacement or by percutaneous transcatheter aortic valve implantation (data from a multicenter Spanish registry)

The factors that influence decision making in severe aortic stenosis (AS) are unknown. Our aim was to assess, in patients with severe AS, the determinants of management and prognosis in a multicenter registry that enrolled all consecutive adults with severe AS during a 1-month period. One-year follow-up was obtained in all patients and included vital status and aortic valve intervention (aortic valve replacement [AVR] and transcatheter aortic valve implantation [TAVI]). A total of 726 patients were included, mean age was 77.3 ± 10.6 years, and 377 were women (51.8%). The most common management was conservative therapy in 468 (64.5%) followed by AVR in 199 (27.4%) and TAVI in 59 (8.1%). The strongest association with aortic valve intervention was patient management in a tertiary hospital with cardiac surgery (odds ratio 2.7, 95% confidence interval 1.8 to 4.1, p <0.001). The 2 main reasons to choose conservative management were the absence of significant symptoms (136% to 29.1%) and the presence of co-morbidity (128% to 27.4%). During 1-year follow-up, 132 patients died (18.2%). The main causes of death were heart failure (60% to 45.5%) and noncardiac diseases (46% to 34.9%). One-year survival for patients treated conservatively, with TAVI, and with AVR was 76.3%, 94.9%, and 92.5%, respectively, p <0.001. One-year survival of patients treated conservatively in the absence of significant symptoms was 97.1%. In conclusion, most patients with severe AS are treated conservatively. The outcome in asymptomatic patients managed conservatively was acceptable. Management in tertiary hospitals is associated with valve intervention. One-year survival was similar with both interventional strategies