Perfil clínico, abordaje y pronóstico del paciente con shock cardiogénico sometido a traslado interhospitalario en España / Clinical profile, management and outcomes of patients with cardiogenic shock undergoing transfer between centers in Spain

Introducción y objetivos El objetivo es analizar el perfil clínico, el abordaje y el pronóstico del shock cardiogénico (SC) por infarto agudo de miocardio con elevación del segmento ST (IAMCEST) que requiere traslado interhospitalario, así como el impacto pronóstico de las variables estructurales de los centros en este contexto. Métodos Se incluyó a los pacientes con SC-IAMCEST atendidos en centros con capacidad de revascularización (2016-2020). Se consideró a: a) pacientes atendidos durante todo el ingreso en hospitales con cardiología intervencionista sin cirugía cardiaca; b) pacientes atendidos en hospitales con cardiología intervencionista y cirugía cardiaca, y c) pacientes trasladados a centros con cardiología intervencionista y cirugía cardiaca. Se analizó la asociación del volumen de SC-IAMCEST atendidos y la disponibilidad de cuidados intensivos cardiológicos (UCIC) y trasplante cardiaco con la mortalidad hospitalaria. Resultados Se incluyeron 4.189 episodios, 1.389 (33,2%) del grupo A, 2.627 del grupo B (62,7%) y 173 del grupo C (4,1%). Los pacientes trasladados eran más jóvenes, tenían más riesgo cardiovascular y recibieron más frecuentemente revascularización, asistencia circulatoria y trasplante cardiaco durante el ingreso (p<0,001). Los pacientes trasladados presentaron menor tasa bruta de mortalidad (el 46,2 frente al 60,3% del grupo A y el 54,4% del grupo B; p<0,001). Mayor volumen asistencial (OR=0,75; p =0,009) y disponibilidad de UCIC (OR=0,80; p =0,047) se asociaron con menor mortalidad. Conclusiones El porcentaje de SC-IAMCEST trasladados en nuestro medio es bajo. Los pacientes trasladados son más jóvenes y reciben más procedimientos invasivos. Los traslados a centros con mayor volumen y UCIC presentan menor mortalidad. (AU)

Introduction and objectives The aim of this study was to analyze the clinical profile, management, and prognosis of ST segment elevation myocardial infarction-related cardiogenic shock (STEMI-CS) requiring interhospital transfer, as well as the prognostic impact of structural variables of the treating centers in this setting. Methods This study included patients with STEMI-CS treated at revascularization-capable centers from 2016 to 2020. The patients were divided into the following groups: group A: patients attended throughout their admission at hospitals with interventional cardiology without cardiac surgery; group B: patients treated at hospitals with interventional cardiology and cardiac surgery; and group C: patients transferred to centers with interventional cardiology and cardiac surgery. We analyzed the association between the volume of STEMI-CS cases treated, the availability of cardiac intensive care units (CICU), and heart transplant with hospital mortality. Results A total of 4189 episodes were included: 1389 (33.2%) from group A, 2627 from group B (62.7%), and 173 from group C (4.1%). Transferred patients were younger, had a higher cardiovascular risk, and more commonly underwent revascularization, mechanical circulatory support, and heart transplant during hospitalization (P<.001). The crude mortality rate was lower in transferred patients (46.2% vs 60.3% in group A and 54.4% in group B, (P<.001)). Lower mortality was associated with a higher volume of care and CICU availability (OR, 0.75, P=.009; and 0.80, P=.047). Conclusions The proportion of transfers in patients with STEMI-CS in our setting is low. Transferred patients were younger and underwent more invasive procedures. Mortality was lower among patients transferred to centers with a higher volume of STEMI-CS cases and CICU. (AU)

Clinical profile, management and outcomes of patients with cardiogenic shock undergoing transfer between centers in Spain.

INTRODUCTION AND OBJECTIVES: The aim of this study was to analyze the clinical profile, management, and prognosis of ST segment elevation myocardial infarction-related cardiogenic shock (STEMI-CS) requiring interhospital transfer, as well as the prognostic impact of structural variables of the treating centers in this setting. METHODS: This study included patients with STEMI-CS treated at revascularization-capable centers from 2016 to 2020. The patients were divided into the following groups: group A: patients attended throughout their admission at hospitals with interventional cardiology without cardiac surgery; group B: patients treated at hospitals with interventional cardiology and cardiac surgery; and group C: patients transferred to centers with interventional cardiology and cardiac surgery. We analyzed the association between the volume of STEMI-CS cases treated, the availability of cardiac intensive care units (CICU), and heart transplant with hospital mortality. RESULTS: A total of 4189 episodes were included: 1389 (33.2%) from group A, 2627 from group B (62.7%), and 173 from group C (4.1%). Transferred patients were younger, had a higher cardiovascular risk, and more commonly underwent revascularization, mechanical circulatory support, and heart transplant during hospitalization (P<.001). The crude mortality rate was lower in transferred patients (46.2% vs 60.3% in group A and 54.4% in group B, (P<.001)). Lower mortality was associated with a higher volume of care and CICU availability (OR, 0.75, P=.009; and 0.80, P=.047). CONCLUSIONS: The proportion of transfers in patients with STEMI-CS in our setting is low. Transferred patients were younger and underwent more invasive procedures. Mortality was lower among patients transferred to centers with a higher volume of STEMI-CS cases and CICU.

Impact of annual volume of cases and intensive cardiac care unit availability on mortality of patients with acute myocardial infarction-related cardiogenic shock treated at revascularization capable centres.

AIMS: Cardiogenic shock (CS) is associated with high mortality. The purpose of this study was to assess the impact of hospital structure-related variables on mortality in patients with CS treated at percutaneous and surgical revascularization capable centres (psRCC) from a large nationwide registry. METHODS AND RESULTS: Retrospective observational study including consecutive patients with main or secondary diagnosis of CS and ST elevation myocardial infarction (STEMI). Patients discharged from Spanish National Healthcare System psRCC were included (2016-20). The association between the volume of CS cases attended by each centre, availability of intensive cardiac care unit (ICCU) and heart transplantation (HT) programmes, and in-hospital mortality was assessed by multilevel logistic regression models. The study population consisted of 3074 CS-STEMI episodes, of whom 1759 (57.2%) occurred in 26 centres with ICCU. A total of 17/44 hospitals (38.6%) were high-volume centres, and 19/44 (43%) centres had HT programmes availability. Treatment at HT centres was not associated with a lower mortality (P = 0.121). Both high volume of cases and ICCU showed a trend to an association with lower mortality in the adjusted model [odds ratio (OR): 0.87 and 0.88, respectively]. The interaction between both variables was significantly protective (OR 0.72; P = 0.024). After propensity score matching, mortality was lower in high-volume hospitals with ICCU (OR 0.79; P = 0.007). CONCLUSION: Most CS-STEMI patients were attended at psRCC with high volume of cases and ICCU available. The combination of high volume and ICCU availability showed the lowest mortality. These data should be taken into account when designing regional networks for CS management.

Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?

Pedigree analysis showed that a large proportion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision. Mitochondrial haplotype appears to be a major factor influencing the risk of vision loss from LHON. Mitochondrial variants, including m.14484T>C and m.11778G>A, have been added to gene arrays, and thus many patients and research participants are tested for LHON mutations. Analysis of the UK Biobank and Australian cohort studies found more than 1 in 1,000 people in the general population carry either the m.14484T>C or the m.11778G>A LHON variant. None of the subset of carriers examined had visual acuity at 20/200 or worse, suggesting a very low penetrance of LHON. Haplogroup analysis of m.14484T>C carriers showed a high rate of haplogroup U subclades, previously shown to have low penetrance in pedigrees. Penetrance calculations of the general population are lower than pedigree calculations, most likely because of modifier genetic factors. This Matters Arising Response paper addresses the Watson et al. (2022) Matters Arising paper, published concurrently in The American Journal of Human Genetics.

Impact of shock aetiology and hospital characteristics on the clinical profile, management and prognosis of patients with non ACS-related cardiogenic shock.

BACKGROUND: A significant proportion of cases of cardiogenic shock (CS) are due aetiologies other than acute coronary syndromes (non ACS-CS). We assessed differences regarding clinical profile, management, and prognosis according to the cause of CS among nonselected patients with CS from a large nationwide database. METHODS: We performed an observational study including patients admitted from the hospitals of the Spanish National Health System (SNHS) with a principal or secondary diagnosis code of CS (2016-2019). Data were obtained from the Minimum Basic Data Set (MBDS). Hospitals were classified according to the availability of cardiology related resources, as well as the availability of Intensive Cardiac Care Unit (ICCU). RESULTS: A total of 10,826 episodes of CS were included, of whom 5,495 (50.8%) were non-ACS related. Non ACS-CS patients were younger (71.5 vs. 72.4 years) and had a lower burden of arteriosclerosis-related comorbidities. Non ACS-CS cases underwent less often invasive procedures and presented lower in-hospital mortality (57.1% vs. 61%,p < 0.001). The most common main diagnosis among non ACS-CS was acute decompensation of chronic heart failure (ADCHF) (35.4%). A lower risk-adjusted in-hospital mortality rate was observed in high volume hospitals (52.6% vs. 56.7%; p < 0.001), as well as in centers with ICCU (OR: 0.71; CI 95%: 0.58-0.87; p < 0.001). CONCLUSIONS: More than a half of cases of CS were due to non-ACS causes. Non ACS-CS cases are a very heterogeneous group, with different clinical profile and management. Management at high-volume hospitals and availability of ICCU were associated with lower risk adjusted mortality among non ACS-CS patients.

Stimulating Mitochondrial Biogenesis with Deoxyribonucleosides Increases Functional Capacity in ECHS1-Deficient Cells.

The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that stimulate mitochondrial biogenesis to boost ATP production. Here, we examined the effects of deoxyribonucleosides (dNs) on mitochondrial biogenesis and function in Short chain enoyl-CoA hydratase 1 (ECHS1) 'knockout' (KO) cells, which exhibit combined defects in both oxidative phosphorylation (OXPHOS) and mitochondrial fatty acid ß-oxidation (FAO). DNs treatment increased mitochondrial DNA (mtDNA) copy number and the expression of mtDNA-encoded transcripts in both CONTROL (CON) and ECHS1 KO cells. DNs treatment also altered global nuclear gene expression, with key gene sets including 'respiratory electron transport' and 'formation of ATP by chemiosmotic coupling' increased in both CON and ECHS1 KO cells. Genes involved in OXPHOS complex I biogenesis were also upregulated in both CON and ECHS1 KO cells following dNs treatment, with a corresponding increase in the steady-state levels of holocomplex I in ECHS1 KO cells. Steady-state levels of OXPHOS complex V, and the CIII2/CIV and CI/CIII2/CIV supercomplexes, were also increased by dNs treatment in ECHS1 KO cells. Importantly, treatment with dNs increased both basal and maximal mitochondrial oxygen consumption in ECHS1 KO cells when metabolizing either glucose or the fatty acid palmitoyl-L-carnitine. These findings highlight the ability of dNs to improve overall mitochondrial respiratory function, via the stimulation mitochondrial biogenesis, in the face of combined defects in OXPHOS and FAO due to ECHS1 deficiency.

Validación del método inverso para la determinación del flujo de acceso con termodilución / Validation of the inverse method for the determination of the access flow with thermodilution

Introducción: La termodilución es un método ampliamente usado para la medición del flujo de acceso vascular (QA). Entre las posibilidades de la termodilución, el método inverso (MI) puede ser beneficioso en el tiempo de ejecución, sin repercusión en la eficacia dialítica (Kt). Sin embargo, no es una técnica lo suficientemente estudiada.MétodoEstudio transversal sobre 117 fístulas arteriovenosas. Se realizaron 2 mediciones de QA con el método descrito por el fabricante (MR) y otra con MI. El MI se basa en la obtención del registro de recirculación invertida al iniciar la sesión y una única medición posterior de recirculación con las líneas en posición normal. En el análisis de concordancia se utilizó el método Bland-Altman y el índice kappa de Cohen.ResultadosSe evidenció muy buena concordancia entre MR y MI para QA inferiores a 700ml/min, pero empeora a medida que aumenta el flujo. La variabilidad mediana entre las mediciones con MR (variabilidad intramétodo) fue del 3,4% (−17,13). Este valor no difirió de la variabilidad mediana generada entre MR y MI (variabilidad intermétodo), que fue del 2% (−14,12) (p=0,287). El grado de acuerdo entre ambos para identificar fístulas arteriovenosas susceptibles de intervención fue muy bueno (kappa=0,834). El tiempo empleado utilizando el MI fue significativamente menor (p=0,000), sin evidenciarse variaciones en el Kt de las sesiones de medida (p=0,201).ConclusionesEl MI de termodilución es válido para determinar el flujo del acceso vascular, especialmente en QA inferiores a 700ml/min, con gran ahorro de tiempo, simplificación del procedimiento y sin modificar la eficacia de diálisis. La variabilidad entre la medición por MR y MI es similar a la propia del MR. La concordancia entre métodos a la hora de identificar fístulas arteriovenosas potencialmente patológicas es muy buena. (AU)

Introduction: Thermodilution is a widely used method for measuring vascular access flow (QA). Among the possibilities of thermodilution, the reverse method (RM) can be beneficial in the execution time, without impact on the dialysis efficacy (Kt). However, it is not a sufficiently studied technique.MethodTransversal study of 117 arteriovenous fistulas. Two QA measurements were taken with the method described by the manufacturer (MR) and another with RM. RM is based on the obtention of an inverted recirculation registry at the beginning of the session and a single subsequent recirculation measurement with the lines in normal position. In the concordance analysis, the Bland-Altman method and Cohen's Kappa index were used.ResultsVery good concordance between MR and RM was evidenced for QA below 700ml/min, but it worsens as flow increases. The median variability between the MR measurements (intra-method variability) was 3.4% (−17.13). This value did not differ from the median variability generated between MR and RM (inter-method variability), which was 2% (−14,12) (P=.287). The degree of agreement between the 2 to identify arteriovenous fistulas susceptible to intervention was very good (Kappa=0.834). The time spent using the RM was significantly shorter (P=.000) without evidence of variations in the Kt of the measurement sessions (P=.201).ConclusionsThe thermodilution RM is valid to determine the flow of the vascular access, especially in QA lower than 700ml/min, with great time savings, simplification of the procedure and without modifying the dialysis efficiency. The variability between the measurement by MR and RM is similar to that of MR. The concordance between methods in identifying potentially pathological arteriovenous fistulas is very good. (AU)

MitoScape: A big-data, machine-learning platform for obtaining mitochondrial DNA from next-generation sequencing data.

The growing number of next-generation sequencing (NGS) data presents a unique opportunity to study the combined impact of mitochondrial and nuclear-encoded genetic variation in complex disease. Mitochondrial DNA variants and in particular, heteroplasmic variants, are critical for determining human disease severity. While there are approaches for obtaining mitochondrial DNA variants from NGS data, these software do not account for the unique characteristics of mitochondrial genetics and can be inaccurate even for homoplasmic variants. We introduce MitoScape, a novel, big-data, software for extracting mitochondrial DNA sequences from NGS. MitoScape adopts a novel departure from other algorithms by using machine learning to model the unique characteristics of mitochondrial genetics. We also employ a novel approach of using rho-zero (mitochondrial DNA-depleted) data to model nuclear-encoded mitochondrial sequences. We showed that MitoScape produces accurate heteroplasmy estimates using gold-standard mitochondrial DNA data. We provide a comprehensive comparison of the most common tools for obtaining mtDNA variants from NGS and showed that MitoScape had superior performance to compared tools in every statistically category we compared, including false positives and false negatives. By applying MitoScape to common disease examples, we illustrate how MitoScape facilitates important heteroplasmy-disease association discoveries by expanding upon a reported association between hypertrophic cardiomyopathy and mitochondrial haplogroup T in men (adjusted p-value = 0.003). The improved accuracy of mitochondrial DNA variants produced by MitoScape will be instrumental in diagnosing disease in the context of personalized medicine and clinical diagnostics.

Establishing risk of vision loss in Leber hereditary optic neuropathy.

We conducted an updated epidemiological study of Leber hereditary optic neuropathy (LHON) in Australia by using registry data to establish the risk of vision loss among different LHON mutations, sex, age at onset, and mitochondrial haplogroup. We identified 96 genetically unrelated LHON pedigrees, including 56 unpublished pedigrees, and updated 40 previously known pedigrees, comprising 620 affected individuals and 4,948 asymptomatic carriers. The minimum prevalence of vision loss due to LHON in Australia in 2020 was one in 68,403 individuals. Although our data confirm some well-established features of LHON, the overall risk of vision loss among those with a LHON mutation was lower than reported previously-17.5% for males and 5.4% for females. Our findings confirm that women, older adults, and younger children are also at risk. Furthermore, we observed a higher incidence of vision loss in children of affected mothers as well as in children of unaffected women with at least one affected brother. Finally, we confirmed our previous report showing a generational fall in prevalence of vision loss among Australian men. Higher reported rates of vision loss in males with a LHON mutation are not supported by our work and other epidemiologic studies. Accurate knowledge of risk is essential for genetic counseling of individuals with LHON mutations. This knowledge could also inform the detection and validation of potential biomarkers and has implications for clinical trials of treatments aimed at preventing vision loss in LHON because an overestimated risk may lead to an underpowered study or a false claim of efficacy.

Validation of the inverse method for the determination of the access flow with thermodilution. / Validación del método inverso para la determinación del flujo de acceso con termodilución.

INTRODUCTION: Thermodilution is a widely used method for measuring vascular access flow (QA). Among the possibilities of thermodilution, the reverse method (RM) can be beneficial in the execution time, without impact on the dialysis efficacy (Kt). However, it is not a sufficiently studied technique. METHOD: Transversal study of 117 arteriovenous fistulas. Two QA measurements were taken with the method described by the manufacturer (MR) and another with RM. RM is based on the obtention of an inverted recirculation registry at the beginning of the session and a single subsequent recirculation measurement with the lines in normal position. In the concordance analysis, the Bland-Altman method and Cohen's Kappa index were used. RESULTS: Very good concordance between MR and RM was evidenced for QA below 700ml/min, but it worsens as flow increases. The median variability between the MR measurements (intra-method variability) was 3.4% (-17.13). This value did not differ from the median variability generated between MR and RM (inter-method variability), which was 2% (-14,12) (P=.287). The degree of agreement between the 2 to identify arteriovenous fistulas susceptible to intervention was very good (Kappa=0.834). The time spent using the RM was significantly shorter (P=.000) without evidence of variations in the Kt of the measurement sessions (P=.201). CONCLUSIONS: The thermodilution RM is valid to determine the flow of the vascular access, especially in QA lower than 700ml/min, with great time savings, simplification of the procedure and without modifying the dialysis efficiency. The variability between the measurement by MR and RM is similar to that of MR. The concordance between methods in identifying potentially pathological arteriovenous fistulas is very good.

Variabilidad intramétodo en medidas del flujo del acceso vascular con termodilución: ¿Un enemigo en los programas de seguimiento? / Intra-method variability in the measurements of vascular access using the thermodilution technique: an enemy in follow-up programs?

OBJETIVO: Analizar el impacto de la variabilidad intramétodo de la Termodilución (TD) en las medidas prospectivas de flujo de acceso (QA) y su relación con los parámetros de seguimiento de primera generación. MÉTODO: Estudio prospectivo. Se realizaron 2 mediciones consecutivas de QA (M1 y M2) y un seguimiento (M3) en 6 meses. Se recogieron datos demográficos y parámetros de seguimiento de primera generación. RESULTADO: Se analizaron 112 fistulas arteriovenosas (-FAV). La mediana de la variabilidad generada entre M1 y M2 no difiere del porcentaje de variación de QA a los 6 meses (p = 0,123). En el 16,8% (14) de los pacientes el QA ha disminuido más del 25% y en un 28,9% (24) aumentó más del 25%. Se evidenció una ligera tendencia a aumentar el porcentaje de descenso de QAa medida que el flujo de las fístulas es mayor (r=-0,229; p = 0,006). Por otra parte, un descenso de QA superior al 25% no se asoció a menor dosis de diálisis (p = 0,183), ni ha aumento significativo de la presión venosa dinámica (p = 0,823) ni al aumento de incidencias durante la punción (p = 0,823). CONCLUSIONES: La presencia de pacientes con aumento de flujo superior a la variabilidad intramétodo y la no asociación entre un descenso superior al 25% y cambios en otros parámetros de seguimiento, hace sospechar la presencia de errores de medición de QA. Frente a ello es conveniente el uso combinado con métodos de primera generación, tanto para establecer el QA basal como para interpretar los descensos en el seguimiento

OBJECTIVE: To analyze the impact of the intra-method variability of thermodilution (TD) in the prospective measurements of the access flow (QA) and the relationship with the first-generation monitoring parameters. METHOD: Prospective study. Two consecutive QAmeasurements (M1 and M2) and a 6-month follow-up (M3) were performed. Demographic data and first-generation follow-up parameters were collected. RESULT: 112 arteriovenous fistulas (AVF) were analyzed. The median variability generated between M1 and M2 does not differ from the percentage of QAvariation at 6 months (p = 0.123). In 16.8% (14) of the patients the QA has decreased by more than 25% and in 28.9% (24) it increased by more than 25%. A slight tendency to increase the percentage of decrease in QA when the fistula flow was higher was evidenced (r=-0.229; p = 0.006). On the other hand, a decrease in QA greater than 25% was not associated with a lower dose of dialysis (p = 0.183), nor did it have a significant increase in dynamic venous pressure (p = 0.823) or an increase in incidences during puncture (p = 0.823). CONCLUSIONS: The presence of patients with an increase in flow greater than the intra-method variability, and the non-association between a decrease greater than 25% and changes in other follow-up parameters, raises suspicions about the presence of QA measurement errors. In relation to this, the combined use with first-generation methods is convenient, both to establish the baseline QA and to interpret the decreases in follow-up

Prevalencia de hipertrigliceridemia en adultos y factores cardiometabólicos asociados. Estudio SIMETAP-HTG / Prevalence of hypertriglyceridemia in adults and related cardiometabolic factors. SIMETAP-HTG study

OBJETIVO: Determinar en la población adulta las tasas de prevalencia brutas y ajustadas por edad y sexo de hipertrigliceridemia (HTG) y valorar su asociación con factores de riesgo cardiovascular, enfermedad renal crónica y enfermedades cardiovasculares y cardiometabólicas. MÉTODOS: Estudio observacional transversal realizado en Atención Primaria, con 6.588 sujetos de estudio adultos, seleccionados aleatoriamente con base poblacional. Los pacientes tenían HTG si la concentración de triglicéridos era≥150mg/dL (≥1,7mmol/L) o estaban en tratamiento hipolipidemiante para reducir los triglicéridos. Se valoraron las asociaciones mediante análisis univariado y multivariante, y se determinaron las prevalencias brutas y ajustadas por edad y sexo. RESULTADOS: Las medias aritméticas y geométricas de las concentraciones de triglicéridos fueron respectivamente 120,5 y 104,2mg/dL en la población global, 135,7 y 116,0mg/dL en hombres, y 108,6 y 95,7mg/dL en mujeres. Las prevalencias brutas de HTG fueron 29,6% en población global, 36,9% en hombres y 23,8% en mujeres. Las prevalencias ajustadas por edad y sexo de HTG fueron 27,0% en población global, 34,6% en hombres y 21,4% en mujeres. Las variables independientes que más se asociaban con la HTG fueron hipercolesterolemia (OR: 4,6), c-HDL bajo (OR: 4,1), esteatosis hepática (OR: 2,8), diabetes (OR: 2,0) y obesidad (OR: 1,9). CONCLUSIONES: Las medias de triglicéridos y las prevalencias de HTG se encuentran intermedias entre las de otros estudios nacionales e internacionales. La quinta parte de la población adulta femenina y más de un tercio de la masculina presentaba HTG. Los factores independientes asociados con HTG fueron hipercolesterolemia y c-HDL bajo, y las variables cardiometabólicas diabetes, esteatosis hepática y obesidad

AIM: To determine in the adult population the crude and the sex- and age-adjusted prevalence rates of hypertriglyceridaemia (HTG) and to assess its association with cardiovascular risk factors, chronic kidney disease, cardiovascular and cardiometabolic diseases. METHODS: Cross-sectional observational study conducted in Primary Care, with 6,588 adult study subjects, randomly selected on base-population. Patients had HTG if the triglyceride level was≥150mg/dL (≥1.7mmol/L), or were on lipid-lowering therapy to lower triglyceride. Associations were assessed by univariate and multivariate analysis, and crude and sex- and age-adjusted prevalence rates were determined. RESULTS: The arithmetic and geometric means of triglyceride levels were respectively 120.5 and 104.2mg/dL in global population, 135.7 and 116.0mg/dL in men, and 108.6 and 95.7mg/dL in women. The crude HTG prevalence rates were 29.6% in global population, 36.9% in men and 23.8% in women. The sex- and age-adjusted HTG prevalence rates were 27.0% in global population, 34.6% in men and 21.4% in women. The independent variables that were most associated with HTG were hypercholesterolemia (OR: 4.6), low HDL-C (OR: 4.1), hepatic steatosis (OR: 2.8), diabetes (OR: 2.0), and obesity (OR: 1.9). CONCLUSIONS: The means of triglyceride levels and HTG prevalence rates are intermediate between those of other national and international studies. A fifth of the female adult population and more than a third of the male population had HTG. The independent factors associated with HTG were hypercholesterolemia and low HDL-C, and the cardiometabolic variables diabetes, hepatic steatosis and obesity

Nuclear response to divergent mitochondrial DNA genotypes modulates the interferon immune response.

Mitochondrial OXPHOS generates most of the energy required for cellular function. OXPHOS biogenesis requires the coordinated expression of the nuclear and mitochondrial genomes. This represents a unique challenge that highlights the importance of nuclear-mitochondrial genetic communication to cellular function. Here we investigated the transcriptomic and functional consequences of nuclear-mitochondrial genetic divergence in vitro and in vivo. We utilized xenomitochondrial cybrid cell lines containing nuclear DNA from the common laboratory mouse Mus musculus domesticus and mitochondrial DNA (mtDNA) from Mus musculus domesticus, or exogenous mtDNA from progressively divergent mouse species Mus spretus, Mus terricolor, Mus caroli and Mus pahari. These cybrids model a wide range of nuclear-mitochondrial genetic divergence that cannot be achieved with other research models. Furthermore, we used a xenomitochondrial mouse model generated in our laboratory that harbors wild-type, C57BL/6J Mus musculus domesticus nuclear DNA and homoplasmic mtDNA from Mus terricolor. RNA sequencing analysis of xenomitochondrial cybrids revealed an activation of interferon signaling pathways even in the absence of OXPHOS dysfunction or immune challenge. In contrast, xenomitochondrial mice displayed lower baseline interferon gene expression and an impairment in the interferon-dependent innate immune response upon immune challenge with herpes simplex virus, which resulted in decreased viral control. Our work demonstrates that nuclear-mitochondrial genetic divergence caused by the introduction of exogenous mtDNA can modulate the interferon immune response both in vitro and in vivo, even when OXPHOS function is not compromised. This work may lead to future insights into the role of mitochondrial genetic variation and the immune function in humans, as patients affected by mitochondrial disease are known to be more susceptible to immune challenges.

Methylation of Ribosomal RNA: A Mitochondrial Perspective.

Ribosomal RNA (rRNA) from all organisms undergoes post-transcriptional modifications that increase the diversity of its composition and activity. In mitochondria, specialized mitochondrial ribosomes (mitoribosomes) are responsible for the synthesis of 13 oxidative phosphorylation proteins encoded by the mitochondrial genome. Mitoribosomal RNA is also modified, with 10 modifications thus far identified and all corresponding modifying enzymes described. This form of epigenetic regulation of mitochondrial gene expression affects mitoribosome biogenesis and function. Here, we provide an overview on rRNA methylation and highlight critical work that is beginning to elucidate its role in mitochondrial gene expression. Given the similarities between bacterial and mitochondrial ribosomes, we focus on studies involving Escherichia coli and human models. Furthermore, we highlight the use of state-of-the-art technologies, such as cryoEM in the study of rRNA methylation and its biological relevance. Understanding the mechanisms and functional relevance of this process represents an exciting frontier in the RNA biology and mitochondrial fields.

OXPHOS bioenergetic compensation does not explain disease penetrance in Leber hereditary optic neuropathy.

Leber hereditary optic neuropathy (LHON) is one of the most common primary mitochondrial diseases. It is caused by point mutations in mitochondrial DNA (mtDNA) genes and in some cases, it can result in irreversible vision loss, primarily in young men. It is currently unknown why LHON mutations affect only some carriers and whether bioenergetic compensation enables unaffected carriers to overcome mitochondrial impairment and preserve cellular function. Here, we conducted bioenergetic metabolic assays and RNA sequencing to address this question using male-only, age-matched, m.11778G > A lymphoblasts and primary fibroblasts from both unaffected carriers and affected individuals. Our work indicates that OXPHOS bioenergetic compensation in LHON peripheral cells does not explain disease phenotype. We show that complex I impairment is similar in cells from unaffected carrier and affected patients, despite a transcriptional downregulation of metabolic pathways including glycolysis in affected cells relative to carriers detected by RNA sequencing. Although we did not detect OXPHOS bioenergetic compensation in carrier cells under basal conditions, our results indicate that cells from affected patients suffer a growth impairment under metabolic challenge compared to carrier cells, which were unaffected by metabolic challenge. If recapitulated in retinal ganglion cells, decreased susceptibility to metabolic challenge in unaffected carriers may help preserve metabolic homeostasis in the face of the mitochondrial complex I bioenergetic defect.

Prevalence of hypertriglyceridemia in adults and related cardiometabolic factors. SIMETAP-HTG study. / Prevalencia de hipertrigliceridemia en adultos y factores cardiometabólicos asociados. Estudio SIMETAP-HTG.

AIM: To determine in the adult population the crude and the sex- and age-adjusted prevalence rates of hypertriglyceridaemia (HTG) and to assess its association with cardiovascular risk factors, chronic kidney disease, cardiovascular and cardiometabolic diseases. METHODS: Cross-sectional observational study conducted in Primary Care, with 6,588 adult study subjects, randomly selected on base-population. Patients had HTG if the triglyceride level was≥150mg/dL (≥1.7mmol/L), or were on lipid-lowering therapy to lower triglyceride. Associations were assessed by univariate and multivariate analysis, and crude and sex- and age-adjusted prevalence rates were determined. RESULTS: The arithmetic and geometric means of triglyceride levels were respectively 120.5 and 104.2mg/dL in global population, 135.7 and 116.0mg/dL in men, and 108.6 and 95.7mg/dL in women. The crude HTG prevalence rates were 29.6% in global population, 36.9% in men and 23.8% in women. The sex- and age-adjusted HTG prevalence rates were 27.0% in global population, 34.6% in men and 21.4% in women. The independent variables that were most associated with HTG were hypercholesterolemia (OR: 4.6), low HDL-C (OR: 4.1), hepatic steatosis (OR: 2.8), diabetes (OR: 2.0), and obesity (OR: 1.9). CONCLUSIONS: The means of triglyceride levels and HTG prevalence rates are intermediate between those of other national and international studies. A fifth of the female adult population and more than a third of the male population had HTG. The independent factors associated with HTG were hypercholesterolemia and low HDL-C, and the cardiometabolic variables diabetes, hepatic steatosis and obesity.

Pioglitazone and Deoxyribonucleoside Combination Treatment Increases Mitochondrial Respiratory Capacity in m.3243A>G MELAS Cybrid Cells.

The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that aim to stimulate mitochondrial biogenesis to boost ATP generation above a critical disease threshold. Here, we examine the effects of the peroxisome proliferator-activated receptor γ (PPARγ) activator pioglitazone (PioG), in combination with deoxyribonucleosides (dNs), on mitochondrial biogenesis in cybrid cells containing >90% of the m.3243A>G mutation associated with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). PioG + dNs combination treatment increased mtDNA copy number and mitochondrial mass in both control (CON) and m.3243A>G (MUT) cybrids, with no adverse effects on cell proliferation. PioG + dNs also increased mtDNA-encoded transcripts in CON cybrids, but had the opposite effect in MUT cybrids, reducing the already elevated transcript levels. Steady-state levels of mature oxidative phosphorylation (OXPHOS) protein complexes were increased by PioG + dNs treatment in CON cybrids, but were unchanged in MUT cybrids. However, treatment was able to significantly increase maximal mitochondrial oxygen consumption rates and cell respiratory control ratios in both CON and MUT cybrids. Overall, these findings highlight the ability of PioG + dNs to improve mitochondrial respiratory function in cybrid cells containing the m.3243A>G MELAS mutation, as well as their potential for development into novel therapies to treat mitochondrial disease.

La oxigenoterapia de alto flujo sí tiene un papel en el tratamiento de la bronquiolitis en las plantas de pediatría / High-flow oxygen therapy does have a role in the treatment of bronchiolitis on the paediatric wards

No disponible