Leukocyte Nuclear Morphology Alterations in Dilated Cardiomyopathy Caused by a Lamin AC Truncating Mutation (LMNA/Ser431*) Are Modified by the Presence of a LAP2 Missense Polymorphism (TMPO/Arg690Cys).

The clinical phenotype of LMNA-associated dilated cardiomyopathy (DCM) varies even among individuals who share the same mutation. LMNA encodes lamin AC, which interacts with the lamin-associated protein 2 alpha (LAP2α) encoded by the TMPO gene. The LAP2α/Arg690Cys polymorphism is frequent in Latin America and was previously found to disrupt LAP2α-Lamin AC interactions in vitro. We identified a DCM patient heterozygous for both a lamin AC truncating mutation (Ser431*) and the LAP2α/Arg690Cys polymorphism. We performed protein modeling and docking experiments, and used confocal microscopy to compare leukocyte nuclear morphology among family members with different genotype combinations (wild type, LAP2α Arg690Cys heterozygous, lamin AC/Ser431* heterozygous, and LAP2α Arg690Cys/lamin AC Ser431* double heterozygous). Protein modeling predicted that 690Cys destabilizes the LAP2α homodimer and impairs lamin AC-LAP2α docking. Lamin AC-deficient nuclei (Ser431* heterozygous) showed characteristic blebs and invaginations, significantly decreased nuclear area, and increased elongation, while LAP2α/Arg690Cys heterozygous nuclei showed a lower perimeter and higher circularity than wild-type nuclei. LAP2α Arg690Cys apparently attenuated the effect of LMNA Ser431* on the nuclear area and fully compensated for its effect on nuclear circularity. Altogether, the data suggest that LAP2α/Arg690Cys may be one of the many factors contributing to phenotype variation of LMNA-associated DCM.

Homozygous Fukutin Missense Mutation in Two Mexican Siblings with Dilated Cardiomyopathy

ABSTRACT Background: Fukuyama congenital muscular dystrophy (FCMD) is the most common form of a group of autosomal recessive disorders characterized by altered α-dystroglycan glycosylation and caused by FKTN gene mutations. However, mutations of this gene may cause a broad range of phenotypes, including Walker-Warburg syndrome, muscle-brain-eye disease, FCMD, limb-girdle muscular dystrophy without mental retardation, and cardiomyopathy with no or minimal skeletal muscle weakness. Objective: Our purpose was to describe two siblings who died at a young age with dilated cardiomyopathy (DCM), no muscle weakness, or atrophy, and were homozygous for a FKTN missense mutation. Methods: Site-directed next-generation sequencing (NGS) was performed. Pathogenicity of variants of interest was established according to the American College of Medical Genetics (ACMG) criteria, and all available first-degree relatives were screened for mutations by Sanger sequencing. Results: NGS revealed a homozygous FKTN variant in the index case (p.Gly424Ser, rs752358445), classified as likely pathogenic by ACMG criteria. Both parents and an unaffected brother were heterozygous carriers. Since the siblings had no apparent skeletal muscle weakness or central nervous system involvement, FKTN mutations were not initially suspected. Conclusions: This is the first report demonstrating that heterozygous individuals for the FKTN p.Gly424Ser mutation were healthy, while two homozygous brothers suffered severe DCM, strongly suggesting that this FKTN mutation is a rare cause of autosomal recessive DCM.

Effectiveness and Safety of Extracorporeal Shockwave Myocardial Revascularization in Patients With Refractory Angina Pectoris and Heart Failure.

Extracorporeal shockwave myocardial revascularization (ESMR) is a therapy for refractory angina pectoris. Our aim was to assess the efficacy and safety of ESMR in the management of patients with stable coronary artery disease (CAD) and heart failure as well as its effects on inflammation and angiogenesis. In this single-arm prospective trial, we included 48 patients with CAD, myocardial ischemia assessed by radionuclide imaging, echocardiographic evidence of left ventricular systolic dysfunction and without revascularization options. Changes in angina grading score, myocardial perfusion, left ventricular ejection fraction, and six-minute walk test after ESMR therapy were used for efficacy assessment. Changes of inflammation and angiogenesis biomarkers were also evaluated. ESMR therapy was performed using a commercially available cardiac shockwave generator system (Cardiospec; Medispec). After 9 weeks of ESMR therapy, a significant improvement was found regarding the initial angina class, severity of ischemia, left ventricular ejection fraction, and six-minute walk test in most patients. No deleterious side effects after treatment were detected. Regarding biomarkers, endothelial progenitor cells and angiopoietin-3 were significantly increased whereas IL-18 and TGF-ß were significantly decreased after ESMR in the total group. Notably, VEGF, IL-1ß, and lipoxin A4 levels were significantly increased only in patients with myocardial ischemia improvement. In conclusion, ESMR therapy is safe and effective in most but not all patients with CAD and heart failure. ESMR is associated with increased markers of angiogenesis and decreased markers of inflammation. Myocardial ischemia improvement after ESMR is associated with increased markers of angiogenesis and pro-resolving mediators.

Homozygous Fukutin Missense Mutation in Two Mexican Siblings with Dilated Cardiomyopathy.

BACKGROUND: Fukuyama congenital muscular dystrophy (FCMD) is the most common form of a group of autosomal recessive disorders characterized by altered α-dystroglycan glycosylation and caused by FKTN gene mutations. However, mutations of this gene may cause a broad range of phenotypes, including Walker-Warburg syndrome, muscle-brain-eye disease, FCMD, limbgirdle muscular dystrophy without mental retardation, and cardiomyopathy with no or minimal skeletal muscle weakness. OBJECTIVE: Our purpose was to describe two siblings who died at a young age with dilated cardiomyopathy (DCM), no muscle weakness, or atrophy, and were homozygous for a FKTN missense mutation. METHODS: Site-directed next-generation sequencing (NGS) was performed. Pathogenicity of variants of interest was established according to the American College of Medical Genetics (ACMG) criteria, and all available first-degree relatives were screened for mutations by Sanger sequencing. RESULTS: NGS revealed a homozygous FKTN variant in the index case (p.Gly424Ser, rs752358445), classified as likely pathogenic by ACMG criteria. Both parents and an unaffected brother were heterozygous carriers. Since the siblings had no apparent skeletal muscle weakness or central nervous system involvement, FKTN mutations were not initially suspected. CONCLUSIONS: This is the first report demonstrating that heterozygous individuals for the FKTN p.Gly424Ser mutation were healthy, while two homozygous brothers suffered severe DCM, strongly suggesting that this FKTN mutation is a rare cause of autosomal recessive DCM.

Genomic study of dilated cardiomyopathy in a group of Mexican patients using site-directed next generation sequencing.

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of nonischemic heart failure and death in young adults. Next generation sequencing (NGS) has become part of the diagnostic workup in idiopathic and familial DCM. More than 50 DCM genes have been identified, revealing great molecular heterogeneity and variable diagnostic yield. Interpretation of variant pathogenicity is challenging particularly in underrepresented populations, as pathogenic variant databases include studies mainly from European/Caucasian populations. To date, no studies on genomic diagnosis of DCM have been conducted in Mexico. METHODS: We recruited 55 unrelated DCM patients, 22 familial (F-DCM), and 33 idiopathic (I-DCM), and performed site-directed NGS seeking causal mutations. Diagnostic yield was defined as the proportion of individuals with at least one pathogenic (P) or likely pathogenic (LP) variant in DCM genes. RESULTS: Overall diagnostic yield was 47.3%, and higher in F-DCM (63.6%) than in I-DCM (36.4%, p = 0.047). Overall, NGS disclosed 41 variants of clinical interest (61.0% novel), 27 were classified as P/LP and 14 of unknown clinical significance. Of P/LP variants, 10 were A-band region TTN truncating variants, five were found in DSP (18.5%), five in MYH7 (18.5%), two in LMNA (7.4%), and one in RBM20, ABCC9, FKTN, ACTA1, and TNNT2. NGS findings suggested autosomal recessive inheritance in three families, two with DSP loss of function mutations in affected individuals. The increasing number of mutation reports in DCM, increasing knowledge on the functional consequences of mutations, mutational hotspots and functional domains of DCM-related proteins, the recent refinement ACMG/ClinGen Guidelines, and co-segregation analysis in DCM families helped increase the diagnostic yield. CONCLUSION: This is the first NGS study performed in a group of Mexican DCM patients, contributing to understand the mutational spectrum and complexity of DCM molecular diagnosis.

[Advances in the pathophysiology and treatment of postoperative pulmonary hypertension]. / Avances en la fisiopatologia y tratamiento de la hipertensión arterial pulmonar postoperatoria grave.

Pulmonary hypertension is a condition frequently seen and associated to many cardiovascular diseases and can become a hemodynamic complication in postoperative period. This can require the integral management in the intensive care room. In the last years we have many new concepts about the pathophysiology of this condition and new therapeutic options. In this paper we review the current strategies for the management of this condition.

Avances en la fisiopatologia y tratamiento de la hipertensión arterial pulmonar postoperatoria grave / Advances in the pathophysiology and treatment of postoperative pulmonary hypertension

Pulmonary hypertension is a condition frequently seen and associated to many cardiovascular diseases and can become a hemodynamic complication in postoperative period. This can require the integral management in the intensive care room. In the last years we have many new concepts about the pathophysiology of this condition and new therapeutic options. In this paper we review the current strategies for the management of this condition.

Uso del levosimendan previo a la cirugía cardíaca, en pacientes con mala función ventricular / Usefulness of levosimendan in patients with ventricular dysfunction before surgery

El propósito de este trabajo fue observar los resultados hemodinámicos inmediatos (primeras 24 hs) en pacientes con mala función ventricular (< 40%), considerados de alto riesgo quirúrgico, en los cuales 24 a 48 hs antes de la cirugía recibían una infusión por 24 hs con levosimendan. Se incluyeron 4 pacientes de sexo masculino con edad promedio de 55.50 (+ 7.93 años) con una fracción de eyección del ventrículo izquierdo de 31 (+ 5.47%), 2 de ellos sometidos a cambio valvular, otro a revascularización miocárdica y el cuarto se sometió a procedimiento combinado (revascularización + cambio valvular). El comportamiento de los parámetros hemodinámicos estuvo estable, sin necesidad de altas dosis de los inotrópicos y vasopresores clásicos en el postoperatorio. Conclusión: El levosimendan podría ser un inotrópico de gran aplicación en este grupo de pacientes debido a su novedoso mecanismo de acción y a sus sostenidos efectos hemodinámicos luego de terminada su infusión.

The purpose of this work was to observe the hemodynamic stability on the first 24 hours in 4 patients with ventricular dysfunction (Ejected Fraction < 40 %), considered of high surgical risk, in which 24 at 48 hr before the surgery received an infusion of Levosimendan for 24 hours. This 4 patients was male, with age 55.5 ± 7.9 years old, a left ventricle ejection of fraction (LVEF) of 31 ± 5.47%; Two of them was underwent to valve replacement, another one to coronary artery bypass graft and the last one patient underwent combined procedure (coronary artery bypass graft surgery and valve replacement). The behavior of the hemodynamic parameters was stable, without necessity of uses high dose of the inotropics and classic vasopresores in the postoperative. Conclusion: the Levosimendan could be an inotropic of great application in this group of patient due to its novel action mechanism and to its sustained hemodynamic effects after having finished its infusion.

[Treatment of perioperative arterial hypertension]. / Tratamiento de la hipertensión arterial perioperatoria.

Pulmonary hypertension (PH) is a condition frequently associated to many cardiovascular diseases and can become a complication in the postoperative period. The success of the treatment depends of the preoperative assessment, an adequate anesthetic and surgical technique and appropriate use of drugs during and after surgery. The presence of PH during the postoperative period can compromise right ventricular function, left ventricular filling and, hence, global perfusion. In recent years, administration of nitric oxide (NO) has been useful for the treatment of cardiovascular conditions associated to pulmonary hypertension. In this paper, we review the current strategies for the management of this condition.

Avances en el tratamiento médico de la insuficiencia cardiaca / Advances in the medical treatment of heart failure

La insuficiencia cardiaca, es una de las entidades con mayor incidencia en los últimos años. Debido al avance en diversas áreas de la práctica cardiológica, cada vez se presenta con mayor frecuencia, lo que ha obligado a un mayor conocimiento de sus mecanismos de progresión y a la investigación de fármacos con la finalidad de aliviar la sintomatología y con ello mejorar la clase funcional de estos enfermos. Desde luego, el tratamiento con medidas dietéticas, tales como baja ingesta de sodio y restricción hídrica se han mantenido en uso durante muchos años, así como diuréticos y digitálicos. Sin embargo, han surgido nuevas alternativas de tratamiento médico, las cuales se analizan en el presente trabajo y que en los años por venir, sin duda serán perfeccionadas e incorporadas al armamentario terapéutico.