m.4216 T > C polymorphism in JT cluster determines a lower pregnancy rate in response to controlled ovarian stimulation treatment.

PURPOSE: To analyze the influence of Caucasian mitochondrial haplogroups on controlled ovarian stimulation outcome (COS), embryo (E), and pregnancy success. METHODS: In a Caucasian population (n = 517) undergoing COS, mitochondrial haplogroups and physiological parameters were determined. Patients were classified, according to Bologna criteria, as good (>3)/poor ≤3) responder, on dependence of recruited oocytes (RO), and in pregnancy/non-pregnancy groups. Haplogroups were determined by sequencing mitochondrial hypervariable sequence I and confirmed by polymerase chain reaction (PCR), followed by restriction fragment length polymorphisms (RFLP). RESULTS: The rank of total dose of FSH (TD FSH) was similar in all clusters/haplogroups, except in JT, which is narrower (950-3,650 IU), particularly in T (1,350-3,650 IU). The statistical analysis showed higher RO and E in JT when compared to U, although it was only Uk which accumulated significantly in pregnancy respect to JT. Pearson's correlations between TD FSH and RO showed negative statistical significance in all population (P = 0.001), H (P = 0.03), JT (P = 0.01), and T (P = 0.03). The percentage of contribution of TD FSH on RO was almost nine times in the JT cluster as compared to all population one. CONCLUSIONS: JT cluster shows a different influence of TD FSH on RO. JT cluster shows higher RO and E than U, but it is Uk which exhibits a significant higher pregnancy rate than JT. The negative influence of the JT cluster on pregnancy success strongly suggests that the m.4216 T > C polymorphism could be responsible.

Variants Ala307Ala and Ser680Ser of 307 and 680 FSHr polymorphisms negatively influence on assisted reproductive techniques outcome and determine high probability of non-pregnancy in Caucasian patients.

PURPOSE: To determine the influence of different genotypes of Ala307Thr and Asn680Ser FSHr polymorphisms on controlled ovarian stimulation (COS) outcome and pregnancy. METHODS: This study collected blood and physiological and clinical parameters of 517 Caucasian patients (Statistical power ≥ 80%) that underwent COS treatment. Genotypes of Ala307Thr and Asn680Ser polymorphisms were determined using PCR amplification followed by Bsu36I and BsrI digestion, respectively. RESULTS: Ala307Ala and Ser680Ser genotypes associated to worse parameters of COS outcome (preovulatory follicles P = 0.05, in both), justifying their lower pregnancy rate than Non-Ala307Ala, P = 0.01 and Non-Ser680Ser, P = 0.004, respectively or together, (P = 0.003). Within the Non-Ala307Ala group, Thr307Thr genotype showed higher number of fertilized oocytes (P = 0.04) and embryos (P = 0.01) than Non-Thr307Thr, but no influence on pregnancy rate. Ala307Ala and Ser680Ser patients doubled probability of non-pregnancy than Non-Ala307Ala (odds ratio = 2.0) and Non-Ser680Ser (odds ratio = 2.11), respectively. Ala307Ala and Ser680Ser genotypes tend to appear together (P < 0.0001), which increases the probability of non-pregnancy. CONCLUSIONS: Ala307Ala and Ser680Ser genotypes of 307 and 680 FSHr polymorphisms associate to worse COS outcome than its respective Non-Ala307Ala and Non-Ser680Ser. Within the Non-Ala307Ala genotypes, Thr307Thr, although shows higher Fertilized Oocytes and Embryos, do not influence on pregnancy rate. Ala307Ala and Ser680Ser genotypes double the probability of Non-Pregnancy than their respective Non-Ala307Ala and Non-Ser680Ser genotypes. Furthermore, the strong tendency of these genotypes to appear together worsens the probability of pregnancy in these patients.

Deepint.net: A Rapid Deployment Platform for Smart Territories.

This paper presents an efficient cyberphysical platform for the smart management of smart territories. It is efficient because it facilitates the implementation of data acquisition and data management methods, as well as data representation and dashboard configuration. The platform allows for the use of any type of data source, ranging from the measurements of a multi-functional IoT sensing devices to relational and non-relational databases. It is also smart because it incorporates a complete artificial intelligence suit for data analysis; it includes techniques for data classification, clustering, forecasting, optimization, visualization, etc. It is also compatible with the edge computing concept, allowing for the distribution of intelligence and the use of intelligent sensors. The concept of smart cities is evolving and adapting to new applications; the trend to create intelligent neighbourhoods, districts or territories is becoming increasingly popular, as opposed to the previous approach of managing an entire megacity. In this paper, the platform is presented, and its architecture and functionalities are described. Moreover, its operation has been validated in a case study where the bike renting service of Paris-Vélib' Métropole has been managed. This platform could enable smart territories to develop adapted knowledge management systems, adapt them to new requirements and to use multiple types of data, and execute efficient computational and artificial intelligence algorithms. The platform optimizes the decisions taken by human experts through explainable artificial intelligence models that obtain data from IoT sensors, databases, the Internet, etc. The global intelligence of the platform could potentially coordinate its decision-making processes with intelligent nodes installed in the edge, which would use the most advanced data processing techniques.

Expanding the clinical phenotypes of MT-ATP6 mutations.

Mitochondrial DNA mutations at MT-ATP6 gene are relatively common in individuals suffering from striatal necrosis syndromes. These patients usually do not show apparent histochemical and/or biochemical signs of oxidative phosphorylation dysfunction. Because of this, MT-ATP6 is not typically analyzed in many other mitochondrial disorders that have not been previously associated to mutations in this gene. To correct this bias, we have performed a screening of the MT-ATP6 gene in a large collection of patients suspected of suffering different mitochondrial DNA (mtDNA) disorders. In three cases, biochemical, molecular-genetics and other analyses in patient tissues and cybrids were also carried out. We found three new pathologic mutations. Two of them in patients showing phenotypes that have not been commonly associated to mutations in the MT-ATP6 gene. These results remark the importance of sequencing the MT-ATP6 gene in patients with striatal necrosis syndromes, but also within other mitochondrial pathologies. This gene should be sequenced at least in all those patients suspected of suffering an mtDNA disorder disclosing normal results for histochemical and biochemical analyses of respiratory chain.

Prognostic value of the tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio in cardiac amyloidosis.

INTRODUCTION AND OBJECTIVES: The tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/SPAP) ratio is a noninvasive surrogate of right ventricular to pulmonary circulation that has prognostic implications in patients with heart failure (HF) or pulmonary hypertension. Our purpose was to evaluate the prognostic value of the TAPSE/SPAP ratio in patients with cardiac amyloidosis. METHODS: We used the database of the AMIGAL study, a prospective, observational registry of patients with cardiac amyloidosis recruited in 7 hospitals of the Autonomous Community of Galicia, Spain, from January 1, 2018 to October 31, 2022. We selected patients whose baseline TAPSE/SPAP ratio was calculated with transthoracic echocardiography. Long-term survival and survival free of HF hospitalization were assessed by means of 5 different multivariable Cox regression models. Median follow-up was 680 days. RESULTS: We studied 233 patients with cardiac amyloidosis, among whom 209 (89.7%) had transthyretin type. The baseline TAPSE/SPAP ratio correlated significantly with clinical outcomes. Depending on the multivariable model considered, the adjusted hazard ratios estimated per 0.1mm/mmHg increase of baseline TAPSE/SPAP ratio ranged from 0.76 to 0.84 for all-cause mortality. Similarly, the ratios for all-cause mortality of HF hospitalization ranged from 0.79 to 0.84. The addition of the baseline TAPSE/SPAP ratio to the predictive model of the United Kingdom National Amyloidosis Centre resulted in an increase in Harrell's c-statistic from 0.662 to 0.705 for all-cause mortality and from 0.668 to 0.707 for all-cause mortality or HF hospitalization. CONCLUSIONS: Reduced TAPSE/SPAP ratio is an independent adverse prognostic marker in patients with cardiac amyloidosis.

[Incidence and causes of hospitalization in patients with transthyretin (ATTR-CA) and light chain (AL-CA) cardiac amyloidosis]. / Incidencia y causas de hospitalización en pacientes con amiloidosis cardiaca por transtiretina (AC-ATTR) y por cadenas ligeras (AC-AL).

INTRODUCTION AND OBJETIVES: Cardiac amyloidosis (CA) is a disorder associated with high number of hospital admissions. Given the scarce information available, we propose an analysis of the incidence and causes of hospitalization in this disease. MATERIAL AND METHODS: One hundred and forty-three patients [128 by transthyretin (ATTR-CA) and 15 by light chains (AL-CA)] included in Registro de Amiloidosis Cardiaca de Galicia (AMIGAL) were evaluated, including all hospitalizations. RESULTS: During a median follow-up of 959 days there were 179 unscheduled hospitalizations [incidence rate (IR) 512.6 admissions per 1000 patients-year], most common due to cardiovascular reasons (n=109, IR 312.2). Most frequent individual cause of hospitalization was heart failure (n=87, TI 249.2). AL-CA was associated with a higher IR of unscheduled hospitalizations than ATTR-CA (IR 781 vs. 483.2; HR 1.62; p=0,029) due to non-cardiovascular admissions (IR 376 vs. 181.2; HR 2.07; p=0.027). Unscheduled admission-free survival at 1 and 3 years in AL-CA was inferior than in ATTR-CA (46.7% and 20.0% vs. 73.4% and 35.2%, respectively; p=0.021). CONCLUSIONS: CA was associated with high incidence of hospitalizations, being heart failure the most frequent individual cause; unscheduled admission-free survival in AL-CA was lower than in ATTR-CA due mostly to non-cardiovascular admissions.

Oxidative phosphorylation differences between mitochondrial DNA haplogroups modify the risk of Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy is a maternally inherited optic atrophy caused by mitochondrial DNA point mutations. Previous epidemiological studies have shown that individuals from mitochondrial genetic backgrounds (haplogroups) J/Uk and H have a higher and a lower risk, respectively, of suffering this disorder. To analyze the bases of these associations at cellular and molecular levels, functional studies with cybrids provide high quality evidence. Cybrids from haplogroup J contain less mitochondrial deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) and synthesize a smaller amount of mitochondrial DNA-encoded polypeptides than those from haplogroup H. Haplogroup J cybrids also display lower oxygen consumption, mitochondrial inner membrane potential and total adenosine-5'-triphosphate (ATP) levels. Moreover, mitochondrial DNA levels correlate with many parameters of the oxidative phosphorylation system. These results suggest that the mitochondrial DNA amount determines oxidative phosphorylation capacity and, along with other recently published observations, support the possibility that mitochondrial DNA levels may be responsible for the bias of the disorder toward males, for the incomplete penetrance of mutations causing Leber's hereditary optic neuropathy and for the association of the disease with particular mitochondrial DNA haplogroups.

'Progress' renders detrimental an ancient mitochondrial DNA genetic variant.

A human mitochondrial DNA (mtDNA) transition, m.1555A>G, in the 12S rRNA gene causes non-syndromic hearing loss. However, this pathological mutation is the wild-type allele in orangutan mtDNA. Here we rule out different genetic factors as the reason for its fixation in orangutans and show that aminoglycosides negatively affect the oxidative phosphorylation function by decreasing the synthesis of mtDNA-encoded proteins and the amount and activity of respiratory complex IV. These drugs also diminish the growth rate of orangutan cells. The m.1555G nucleotide is also the wild-type allele in other mammal species and they might be at risk of suffering a mitochondrial disorder if treated with aminoglycosides. Therefore, pharmacogenomic approaches should be used to confirm this possibility. These observations are important for human health. Due to the fact that old age and high frequency are criteria widely used in mitochondrial medicine to rule out a genetic change as being a pathological mutation, our results prevent against simplistic genetic approaches that do not consider the potential effect of environmental conditions. Hence, these results suggest that some ancient and highly frequent human population polymorphisms, such as those defining mtDNA haplogroups, in mitochondrial rRNA genes can be deleterious in association with new environmental conditions. Therefore, as the discovery of ribosomal antibiotics has allowed to fight infectious diseases and this breakthrough can be considered an important scientific advance or 'progress', our results suggest that 'progress' can also have a negative counterpart and render detrimental many of these mtDNA genotypes.

Safety and feasibility of transradial access for percutaneous coronary intervention in chronic total occlusions.

INTRODUCTION AND OBJECTIVES: Transfemoral access is the most frequently used vascular approach in chronic total occlusion percutaneous coronary interventions (CTO-PCI). The aim of this study was to evaluate the safety and feasibility of a transradial access CTO-PCI program and its impact on angiographic and clinical results and length of hospital stay. METHODS: Retrospective multicenter cohort study including 2550 consecutive CTO-PCI procedures included in a multicenter registry with accurate information on vascular access. A total of 896 procedures were performed as radial-only access while 1654 were performed through at least 1 femoral puncture. Clinical and angiographic data were collected. RESULTS: The mean age was 66.3± 11.4 years. The mean Japan-chronic total occlusion score (2.7±0.3) was similar in the 2 groups. Successful revascularization was achieved in 2009 (79.6%) cases, 78.2% and 82.1% in the femoral and radial access cohorts, respectively (P=.002). Periprocedural in-hospital complications were observed in 5.1% and 2.3% (P=.02), with fewer access site-dependant vascular complications in the transradial cohort (2.3% vs 0.2%; P=.009). The mean length of hospital stay was significantly shorter in the transradial access group (0.89±1.4 vs 2.2±3.2 days, P<.001). CONCLUSIONS: A transradial program for CTO-PCI is safe and effective in most CTO lesions. The transradial strategy has fewer vascular complications and shorter length of hospital stay without compromising the success rate.

Unmasking the causes of multifactorial disorders: OXPHOS differences between mitochondrial haplogroups.

Many epidemiologic studies have associated human mitochondrial haplogroups to rare mitochondrial diseases like Leber's hereditary optic neuropathy or to more common age-linked disorders such as Parkinson's disease. However, cellular, biochemical and molecular-genetic evidence that is able to explain these associations is very scarce. The etiology of multifactorial diseases is very difficult to sort out because such diseases are due to a combination of genetic and environmental factors that individually only contribute in small part to the development of the illness. Thus, the haplogroup-defining mutations might behave as susceptibility factors, but they could have only a small effect on oxidative phosphorylation (OXPHOS) function. Moreover, these effects would be highly dependent on the 'context' in which the genetic variant is acting. To homogenize this 'context' for mitochondrial DNA (mtDNA) mutations, a cellular approach is available that involves the use of what is known as 'cybrids'. By using this model, we demonstrate that mtDNA and mtRNA levels, mitochondrial protein synthesis, cytochrome oxidase activity and amount, normalized oxygen consumption, mitochondrial inner membrane potential and growth capacity are different in cybrids from the haplogroup H when compared with those of the haplogroup Uk. Thus, these inherited basal differences in OXPHOS capacity can help to explain why some individuals more quickly reach the bioenergetic threshold below which tissue symptoms appear and progress toward multifactorial disorders. Hence, some population genetic variants in mtDNA contribute to the genetic component of complex disorders. The existence of mtDNA-based OXPHOS differences opens possibilities for the existence of a new field, mitochondrial pharmacogenomics. New sequence accession nos: HM103354-HM103363.

Impact of electrocardiographic interpretability on outcome in patients referred for stress testing.

BACKGROUND: There is limited insight into the association of electrocardiographic interpretability with outcome in patients referred for stress testing. METHODS: Exercise echocardiography was performed in 8226 patients with known or suspected coronary artery disease. Electrocardiograms were considered uninterpretable in the presence of left bundle-branch block (LBBB), left ventricular hypertrophy (LVH) with strain, repolarization abnormalities because of digitalis therapy, ventricular paced rhythm, preexcitation or ST depression ≥ 0.1 mV because of other causes. End points were all-cause mortality, cardiac death and hard cardiac events (i.e. cardiac death or nonfatal myocardial infarction). RESULTS: A total of 2450 patients had uninterpretable electrocardiograms. During a follow-up period of 4.1 ± 3.5 years, there were 1011 deaths (of which 478 were cardiac deaths) and 1069 patients experienced a hard cardiac event. The 5-year rates of death, cardiac death and hard cardiac events were, respectively, 18.7%, 10.9% and 18.8% in patients with uninterpretable ECGs, compared with 9.5%, 4.1% and 10.9% in those with interpretable ECGs (P < 0.001). After covariate adjustment, lack of ECG interpretability remained an independent predictor of all-cause mortality (hazard ratio [HR] 1.25, 95% confidence interval [CI] 1.08-1.44, P = 0.002), cardiac death (HR 1.63, 95% CI 1.32-2.01, P < 0.001) and hard cardiac events (HR 1.28, 95% CI 1.11-1.47, P < 0.001). When the specific ECG abnormalities were included as covariates, LBBB, LVH and digitalis therapy remained predictors of cardiac death; LBBB and LVH were predictors of hard cardiac events, and LVH remained predictive of all-cause mortality. CONCLUSION: Uninterpretable ECGs portend a worse prognosis in patients referred for stress testing.

Cardiac amyloidosis: Description of a series of 143 cases. / Amiloidosis cardiaca: descripción de una serie de 143 casos.

INTRODUCTION AND OBJECTIVES: Recently, there have been important advances in the diagnosis and treatment of cardiac amyloidosis (CA). Our aim was to provide an updated description of its 2 most frequent types: the transthyretin CA (ATTR-CA) and the light chain CA (AL-CA). METHODS: Prospective registry of patients with CA diagnosed in 7 institutions in Galicia (Spain) between January 1, 2018 and June 30, 2020. Variables related to clinical characteristics, complementary tests, survival and causes of death were collected. RESULTS: One hundred and forty-three patients with CA were consecutively included, 128 ATTR-CA (89.5%) and 15 AL-CA (10.5%). Mean age was 79.6±7.7 years and 23.8% were women. Most patients with ATTR-CA were diagnosed non-invasively (87.5%). On physical examination, 35.7, 35 and 7% had Popeye's sign, Dupuytren's contracture and macroglossia, respectively. Twelve-month and 24-month survival was 92.1 and 76.2% in the ATTR-CA group, and 78.6 and 61.1% in the AL-CA group (P=.152). The cause of death was cardiovascular in 80.8% of the cohort. CONCLUSIONS: ATTR-CA can be diagnosed non-invasively in most cases and it is the most common type of CA in routine clinical practice. Furthermore, an increase in the short-term survival of CA appears to be observed, which could be due to advances related to its diagnosis and treatment.

Syncope in patients with transthyretin amyloid cardiomyopathy: clinical features and outcomes.

BACKGROUND: We aimed to describe the clinical characteristics, underlying causes and outcomes of syncope in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). METHODS: The clinical profile and underlying causes of syncopal episodes were reviewed in a cohort of 128 patients with ATTR-CM enrolled from January 2018 to June 2020 in a prospective multicentre registry in 7 hospitals of Galicia (Spain). After enrollment, patients were followed during a median period of 520 days. The effect of syncope on all-cause mortality was assessed by means of multivariate Cox´s regression. RESULTS: Thirty (23.4%) patients had a history of previous syncope as a clinical antecedent before being enrolled in the prospective phase of the registry, and 4 (3.1%) experienced a first episode of syncope thereafter. The estimated incidence density rate of syncope during the prospective follow-up period after registry enrollment was 71.9 episodes per 1000 patients-year (95% Confidence Interval (CI) 32.8-111.1). The estimated overall prevalence of syncope was 26.6% (95% CI 18.9%-34.2%). Cardiac arrhythmias (n = 11, 32.3%), structural diseases of the heart or great vessels (n = 5, 14.7%), a neurally mediated reflex (n = 6, 17.6%), and orthostatic hypotension (n = 4, 11.8%) were identified as probable underlying causes of syncope; in 8 (23.6%) patients, syncope remained unexplained. Patients with syncope had increased non-adjusted all-cause mortality than patients without it (univariate hazard-ratio 3.37; 95% CI 1.43-7.94). When other independent predictors of survival were added to the survival model, this association was no longer statistically significant (multivariate hazard-ratio 1.81, 95% CI 0.67-4.84). CONCLUSIONS: Syncope is frequent in patients with ATTR-CM. This study could not demonstrate an independent association between syncope and mortality in those individuals.Abbreviations: ATTR-CM: Transthyretin amyloid cardiomyopathy; CI: Confidence Interval; HF: Heart Failure; HR: Hazard Ratio; IQR: Interquartile rank; LVEF: Left Ventricular Ejection Fraction; NTproBNP: N-terminal pro-brain natriuretic peptide; SD: Standard Deviation; 99mTc-DPD: technetium-99m-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid.

Beta-Blocker Exposure and Survival in Patients With Transthyretin Amyloid Cardiomyopathy.

OBJECTIVE: To investigate a potential association between beta-blocker exposure and survival in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). METHODS: In this real-world prospective registry of 128 consecutive patients with ATTR-CM recruited in 7 institutions in Galicia (Spain), survival of 65 patients who received beta blockers on registry enrollment was compared with that of 63 untreated controls by means of both unweighted Cox regression and Cox regression with inverse probability of treatment weighting. Tolerance to and adverse effects of beta blockers were recorded. Median study follow-up was 520 days. RESULTS: Patients with ATTR-CM who received beta blockers showed statistically significant lower all-cause mortality than untreated controls as evaluated by either unweighted Cox regression (hazard ratio, 0.31; 95% CI, 0.12 to 0.79) or Cox regression with inverse probability of treatment weighting (hazard ratio, 0.18; 95% CI, 0.08 to 0.41; P<.001). Several sensitivity analyses confirmed the internal validity of these results. The overall frequency of beta-blocker suspension due to adverse effects was 25% (95% CI, 15.5% to 34.5%). CONCLUSION: In this real-world, prospective, multi-institutional registry, patients with ATTR-CM who received beta blockers had lower all-cause mortality than untreated controls.

Adjusting RFR by Predictors of Disagreement, "The Adjusted RFR": An Alternative Methodology to Improve the Diagnostic Capacity of Coronary Indices. / Ajustando a RFR por Preditores de Discordância, "A RFR Ajustada": Uma Metodologia Alternativa para Melhorar a Capacidade Diagnóstica dos Índices Coronarianos.

BACKGROUND: Cutoff thresholds for the "resting full-cycle ratio" (RFR) oscillate in different series, suggesting that population characteristics may influence them. Likewise, predictors of discordance between the RFR and fractional flow reserve (FFR) have been documented. The RECOPA Study showed that diagnostic capacity is reduced in the RFR "grey zone", requiring the performance of FFR to rule out or confirm ischemia. OBJECTIVES: To determine predictors of discordance, integrate the information they provide in a clinical-physiological index, the "Adjusted RFR", and compare its agreement with the FFR. METHODS: Using data from the RECOPA Study, predictors of discordance with respect to FFR were determined in the RFR "grey zone" (0.86 to 0.92) to construct an index ("Adjusted RFR") that would weigh RFR together with predictors of discordance and evaluate its agreement with FFR. RESULTS: A total of 156 lesions were evaluated in 141 patients. Predictors of discordance were: chronic kidney disease, previous ischemic heart disease, lesions not involving the anterior descending artery, and acute coronary syndrome. Though limited, the "Adjusted RFR" improved the diagnostic capacity compared to the RFR in the "grey zone" (AUC-RFR = 0.651 versus AUC-"Adjusted RFR" = 0.749), also showing an improvement in all diagnostic indices when optimal cutoff thresholds were established (sensitivity: 59% to 68%; specificity: 62% to 75%; diagnostic accuracy: 60% to 71%; positive likelihood ratio: 1.51 to 2.34; negative likelihood ratio: 0.64 to 0.37). CONCLUSIONS: Adjusting the RFR by integrating the information provided by predictors of discordance to obtain the "Adjusted RFR" improved the diagnostic capacity in our population. Further studies are required to evaluate whether clinical-physiological indices improve the diagnostic capacity of RFR or other coronary indices.

FUNDAMENTO: Os limiares de corte para a "relação do ciclo completo de repouso" (RFR) oscilam em diferentes séries, sugerindo que as características da população podem influenciá-los. Da mesma forma, foram documentados preditores de discordância entre a RFR e a reserva de fluxo fracionado (FFR). O Estudo RECOPA, mostrou que a capacidade diagnóstica está reduzida na "zona cinzenta" da RFR, tornando necessária a realização de FFR para descartar ou confirmar isquemia. OBJETIVOS: Determinar os preditores de discordância, integrar as informações que eles fornecem em um índice clínico-fisiológico: a "RFR Ajustada", e comparar sua concordância com o FFR. MÉTODOS: Usando dados do Estudo RECOPA, os preditores de discordância em relação à FFR foram determinados na "zona cinzenta" da RFR (0,86 a 0,92) para construir um índice ("RFR Ajustada") que pesaria a RFR juntamente com os preditores de discordância e avaliar sua concordância com a FFR. RESULTADOS: Foram avaliadas 156 lesões em 141 pacientes. Os preditores de discordância foram: doença renal crônica, cardiopatia isquêmica prévia, lesões não envolvendo a artéria descendente anterior esquerda e síndrome coronariana aguda. Embora limitada, a "RFR Ajustada" melhorou a capacidade diagnóstica em comparação com a RFR na "zona cinzenta" (AUC-RFR = 0,651 versus AUC-"RFR Ajustada" = 0,749), mostrando também uma melhora em todos os índices diagnósticos quando foram estabelecidos limiares de corte otimizados (sensibilidade: 59% a 68%; especificidade: 62% a 75%; acurácia diagnóstica: 60% a 71%; razão de verossimilhança positiva: 1,51 a 2,34; razão de verossimilhança negativa: 0,64 a 0,37). CONCLUSÕES: Ajustar a RFR integrando as informações fornecidas pelos preditores de discordância para obter a "RFR Ajustada" melhorou a capacidade diagnóstica em nossa população. Mais estudos são necessários para avaliar se os índices clínico-fisiológicos melhoram a capacidade diagnóstica da RFR ou de outros índices coronarianos.

Plaque modification in calcified chronic total occlusions: the PLACCTON study.

INTRODUCTION AND OBJECTIVES: Severe calcification is present in> 50% of coronary chronic total occlusions (CTOs) undergoing percutaneous intervention. We aimed to describe the contemporary use and outcomes of plaque modification devices (PMDs) in this context. METHODS: Patients were included in the prospective, consecutive Iberian CTO registry (32 centers in Spain and Portugal), from 2015 to 2020. Comparison was performed according to the use of PMDs. RESULTS: Among 2235 patients, wire crossing was achieved in 1900 patients and PMDs were used in 134 patients (7%), requiring more than 1 PMD in 24 patients (1%). The selected PMDs were rotational atherectomy (35.1%), lithotripsy (5.2%), laser (11.2%), cutting/scoring balloons (27.6%), OPN balloons (2.9%), or a combination of PMDs (18%). PMDs were used in older patients, with greater cardiovascular burden, and higher Syntax and J-CTO scores. This greater complexity was associated with longer procedural time but similar total stent length (52 vs 57mm; P=.105). If the wire crossed, the procedural success rate was 87.2% but increased to 96.3% when PMDs were used (P=.001). Conversely, PMDs were not associated with a higher rate of procedural complications (3.7 vs 3.2%; P=.615). Despite the worse baseline profile, at 2 years of follow-up there were no differences in the survival rate (PMDs: 94.3% vs no-PMDs: 94.3%, respectively; P=.967). CONCLUSIONS: Following successful wire crossing in CTOs, PMDs were used in 7% of the lesions with an increased success rate. Mid-term outcomes were comparable despite their worse baseline profile, suggesting that broader use of PMDs in this setting might have potential technical and prognostic benefits.

20 years of human mtDNA pathologic point mutations: carefully reading the pathogenicity criteria.

Despite the strong purifying selection that occurs during embryonic development, the particular location and features of mitochondrial DNA make it especially susceptible to accumulating point mutations, giving rise to a large number of mitochondrial DNA variants. Many of these will have moderate or no phenotypic effects but others will be the cause of very dramatic diseases, usually known as mitochondriopathies. Because of the abundance of different mitochondrial DNA variants, it is not easy to determine whether a new mutation is pathogenic. To facilitate this task, different criteria have been proposed, but they are often either too severely or too loosely applied. Citing examples from the literature, in this paper we discuss some critical aspects of these criteria.

Human mitochondrial variants influence on oxygen consumption.

This work investigates if human mitochondrial variants influence on maximal oxygen consumption (VO(2max)). With this purpose we recruited, as a uniform population in term of nutritional habits and life style, 114 healthy male Spanish subjects that practiced fitness exercises 3-4 times a week. Once mtDNA haplogroups were determined, we found that J presents with lower VO(2max) (P=0.02) than nonJ variants. J has been related with a lower efficiency of electron transport chain (ETC), diminished ATP and ROS production. Thus, the difficult to compensate the mitochondrial energetic deficiency could explain the accumulation of J haplogroup in LHON and multiple sclerosis. Furthermore, the lower ROS production associated to J could also account for the accrual of this variant in elderly people consequent to a decreased oxidative damage.

Association of mitochondrial haplogroup J and mtDNA oxidative damage in two different North Spain elderly populations.

This work investigates the association between longevity, mitochondrial DNA (mtDNA) variants and oxidative DNA damage in an older than 85 years population. The participants, similar in genetic and cultural background as well as gender distribution, come from villages near to the Pyrenees Mountains (900-1,400 m altitude) (n = 69) and the Ebro's Valley (200-300 m altitude) (n = 69) in Spain. Our results show an accumulation of the haplogroup J in elderly individuals with an over-representation of J2 in Pyrenees group but not in the Ebro's Valley, the former associating with a diminished DNA damage. In conclusion, our results suggest that J mitochondrial variant, that induce lower mtDNA damage, could present a phenotypic survival advantage to environmental conditions and, thus, accumulate in elderly population.

Cisplatin-mediated impairment of mitochondrial DNA metabolism inversely correlates with glutathione levels.

Cisplatin accumulates in mitochondria, which are a major target for this drug in cancer cells. Thus alterations in mitochondrial function have been implicated in cancer cell resistance to chemotherapeutic agents. Moreover, cisplatin toxic side effects seem to be associated with mitochondrial injury in vivo and in vitro. In order to clarify the potential effect of cisplatin in mtDNA (mitochondrial DNA) maintenance and expression, we have analysed rat liver mtDNA and mtRNA (mitochondrial RNA) synthesis as well as their stability under the influence of in vivo treatment or in vitro exposure to cisplatin. We show that cisplatin causes a direct and significant impairment of mtDNA and mtRNA synthesis and decreases steady-state levels of mtRNAs in isolated mitochondria. Furthermore, in vivo treatment of the animals with cisplatin exerts a protective effect from the impairment of mtRNA metabolism caused by in vitro exposure to the drug, by means of increased mitochondrial GSH levels after in vivo cisplatin treatment.