Sex Differences in Transthyretin Cardiac Amyloidosis: Unraveling the Complexities in Epidemiology, Pathophysiology, Diagnosis, and Treatment.

Transthyretin cardiac amyloidosis (ATTR-CA) is characterised by the deposition of transthyretin amyloid fibrils in the heart. ATTR-CA affects both men and women although there is evidence of sex differences in prevalence and clinical presentation. PURPOSE OF REVIEW: This review paper aims to comprehensively examine and synthesise the existing literature on sex differences in ATTR-CA. RECENT FINDINGS: The prevalence of ATTR-CA is higher in males although the male predominance is more apparent in older patients in the wild type form and in TTR genetic variants that predominantly result in a cardiac phenotype in the hereditary variant. Women tend to have less left ventricular hypertrophy (LVH) and a higher ejection fraction at clinical presentation which may contribute to a later diagnosis although the prognosis appears to be similar in both sexes. Female sex is a predictor of a good response to tafamidis 20 mg in TTR polyneuropathy but otherwise there are no data on sex differences in the efficacy of other treatments for ATTR-CA. It is crucial to define specific sex differences in ATTR-CA. A lower cut-off value for LVH in women may be needed to improve diagnosis. It is necessary to increase female representation in clinical trials to better understand possible sex differences in therapeutic management.

Increased Chamber Resting Tone Is a Key Determinant of Left Ventricular Diastolic Dysfunction.

BACKGROUND: Twitch-independent tension has been demonstrated in cardiomyocytes, but its role in heart failure (HF) is unclear. We aimed to address twitch-independent tension as a source of diastolic dysfunction by isolating the effects of chamber resting tone (RT) from impaired relaxation and stiffness. METHODS: We invasively monitored pressure-volume data during cardiopulmonary exercise in 20 patients with hypertrophic cardiomyopathy, 17 control subjects, and 35 patients with HF with preserved ejection fraction. To measure RT, we developed a new method to fit continuous pressure-volume measurements, and first validated it in a computational model of loss of cMyBP-C (myosin binding protein-C). RESULTS: In hypertrophic cardiomyopathy, RT (estimated marginal mean [95% CI]) was 3.4 (0.4-6.4) mm Hg, increasing to 18.5 (15.5-21.5) mm Hg with exercise (P<0.001). At peak exercise, RT was responsible for 64% (53%-76%) of end-diastolic pressure, whereas incomplete relaxation and stiffness accounted for the rest. RT correlated with the levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide; R=0.57; P=0.02) and with pulmonary wedge pressure but following different slopes at rest and during exercise (R2=0.49; P<0.001). In controls, RT was 0.0 mm Hg and 1.2 (0.3-2.8) mm Hg in HF with preserved ejection fraction patients and was also exacerbated by exercise. In silico, RT increased in parallel to the loss of cMyBP-C function and correlated with twitch-independent myofilament tension (R=0.997). CONCLUSIONS: Augmented RT is the major cause of LV diastolic chamber dysfunction in hypertrophic cardiomyopathy and HF with preserved ejection fraction. RT transients determine diastolic pressures, pulmonary pressures, and functional capacity to a greater extent than relaxation and stiffness abnormalities. These findings support antimyosin agents for treating HF.

Invasive management of significant tricuspid regurgitation in clinical practice.

BACKGROUND: Tricuspid regurgitation (TR) is a prevalent condition inside valvular heart disease (VHD) with relevant prognosis implications. However, concordance between real management in clinical practice and invasive treatment recommendations of European Society of Cardiology (ESC) guidelines is unknown. METHODS: A substudy of ESC VHD II survey was performed to evaluate the real treatment of TR compared to the clinical ESC guidelines recommendations published in 2012, 2017 and 2021 was performed. TR cases with surgical indication were divided in 3 groups: 1: severe isolated TR without previous left VHD; 2: moderate/severe TR and concomitant severe left VHD; 3: severe TR plus previous left VHD surgery. RESULTS: Of 902 patients assessed, 123 had significant TR. Fifty (41%) cases demonstrated ESC guidelines 2012-2017 Class I or IIa recommendations for invasive treatment: 9(18%) of group 1, 37(74%) of group 2 and 4(8%) of group 3. Surgery was performed in 24 patients (48%); 1 in group 1(4%), 22 in group 2(92%) and 1 in group 3(4%). Overall concordance was 48% (group 1: 11%; group 2: 59%; group 3: 25%). Regarding the 2021 ESC guidelines only one patient changed groups with an overall concordance of 47% (group 1: 10%; group 2: 59%; group 3: 25%). CONCLUSION: Concordance between 2012, 2017 and 2021 ESC guidelines recommendations and clinical practice for TR surgical intervention is low, especially in those without concomitant severe left VHD. These results suggest the need to improve further guideline implementation and alternative treatments, such as percutaneous, which could resolve potential discrepancies in those clinical scenarios.

Natural History of MYH7-Related Dilated Cardiomyopathy.

BACKGROUND: Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVES: We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS: We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 ± 19.2 years) recruited from 29 international centers. RESULTS: At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% ± 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of ≤35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS: MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare.

Evaluating the effectiveness of a comprehensive patient education intervention in a hybrid model of cardiac rehabilitation: A pilot study.

Objective: To evaluate the effectiveness of a comprehensive educational intervention in a hybrid model of cardiac rehabilitation in Spain during the COVID-19 pandemic. Methods: In a prospective pretest-posttest pilot study a pooled sample of patients attending hybrid cardiac rehabilitation in Spain received a culturally-adapted education intervention for 6 weeks. Participants completed surveys at pre- and post-rehabilitation assessing disease-related knowledge, health literacy, adherence to the Mediterranean Diet and self-efficacy. Physical activity was measured by number of steps per day using wearable activity tracking devices. Satisfaction with the educational materials was also evaluated by a survey with a 10 point Likert-type scale and yes/no and open-ended questions. Results: Eighty-one(99%) participants completed both assessments. There was significant improvement in disease-related knowledge(p < 0.001), physical activity(p < 0.001), and adherence to the diet(p = 0.005) post-rehabilitation. The number of participants that were classified as having "high health literacy skills" increased by 17%. Post-rehabilitation knowledge was associated with education level (ß = 0.430; p = 0.001),pre-rehabilitation knowledge (ß = 0.510; p = 0.002), and high health literacy skills (ß = 0.489; p = 0.01). Educational materials were highly satisfactory to participants. Conclusion: Significant increases in disease-related knowledge and health behaviors in patients attending hybrid models of cardiac rehabilitation are encouraging results that support the value of implementing comprehensive educational initiatives to programs in Spain. Innovation: This work presents preliminary evidence of the effectiveness of the first comprehensive education intervention that is open access and culturally adapted to people living with cardiovascular disease in Spain.

Association of Genetic Variants With Outcomes in Patients With Nonischemic Dilated Cardiomyopathy.

BACKGROUND: The clinical relevance of genetic variants in nonischemic dilated cardiomyopathy (DCM) is unsettled. OBJECTIVES: The study sought to assess the prognostic impact of disease-causing genetic variants in DCM. METHODS: Baseline and longitudinal clinical data from 1,005 genotyped DCM probands were retrospectively collected at 20 centers. A total of 372 (37%) patients had pathogenic or likely pathogenic variants (genotype positive) and 633 (63%) were genotype negative. The primary endpoint was a composite of major adverse cardiovascular events. Secondary endpoints were end-stage heart failure (ESHF), malignant ventricular arrhythmia (MVA), and left ventricular reverse remodeling (LVRR). RESULTS: After a median follow-up of 4.04 years (interquartile range: 1.70-7.50 years), the primary endpoint had occurred in 118 (31.7%) patients in the genotype-positive group and in 125 (19.8%) patients in the genotype-negative group (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.17-1.94; P = 0.001). ESHF occurred in 60 (16.1%) genotype-positive patients and in 55 (8.7%) genotype-negative patients (HR: 1.67; 95% CI: 1.16-2.41; P = 0.006). MVA occurred in 73 (19.6%) genotype-positive patients and in 77 (12.2%) genotype-negative patients (HR: 1.50; 95% CI: 1.09-2.07; P = 0.013). LVRR occurred in 39.6% in the genotype-positive group and in 46.2% in the genotype-negative group (P = 0.047). Among individuals with baseline left ventricular ejection fraction ≤35%, genotype-positive patients exhibited more major adverse cardiovascular events, ESHF, and MVA than their genotype-negative peers (all P < 0.02). LVRR and clinical outcomes varied depending on the underlying affected gene. CONCLUSIONS: In this study, DCM patients with pathogenic or likely pathogenic variants had worse prognosis than genotype-negative individuals. Clinical course differed depending on the underlying affected gene.

Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males.

OBJECTIVE: One of the challenges in hypertrophic cardiomyopathy (HCM) is to determine the pathogenicity of genetic variants and to establish genotype/phenotype correlations. This study aimed to: (1) demonstrate that MYBPC3 c.2149-1G>A is a founder pathogenic variant, (2) describe the phenotype and clinical characteristics of mutation carriers and (3) compare these patients with those with the most frequent pathogenic HCM variants: MYBPC3 p.Arg502Trp/Gln. METHODS: We reviewed genetic tests performed in HCM probands at our institution. We carried out transcript analyses to demonstrate the splicing effect, and haplotype analyses to support the founder effect of MYBPC3 c.2149-1G>A. Carriers with this mutation were compared with those from MYBPC3 p.Arg502Trp/Gln in terms of presentation features, imaging and outcomes. RESULTS: MYBPC3 c.2149-1G>A was identified in 8 of 570 probands and 25 relatives. Penetrance was age and sex dependent, 50.0% of the carriers over age 36 years and 75.0% of the carriers over 40 years showing HCM. Penetrance was significantly higher in males: in carriers older than 30 years old, 100.0% of males vs 50.0% of females had a HCM phenotype (p=0.01). Males were also younger at diagnosis (32±13 vs 53±10 years old, p<0.001). MYBPC3 c.2149-1G>A resulted in an abnormal transcript that led to haploinsufficiency and was segregated in two haplotypes. However, both came from one founder haplotype. Affected carriers showed a better functional class and higher left ventricular ejection fraction (LVEF) than patients with MYBPC3 p.Arg502Trp/Gln (p<0.05 for both). Nevertheless, the rate of major adverse outcomes was similar between the two groups. CONCLUSIONS: MYBPC3 c.2149-1G>A splicing variant is a founder mutation. Affected males show an early onset of HCM and with higher penetrance than women. Carriers show better functional class and higher LVEF than MYBPC3 p.Arg502Trp/Gln carriers, but a similar rate of major adverse outcomes.

Predictors of outcome in a Spanish cohort of patients with Fabry disease on enzyme replacement therapy.

Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT. STUDY DESIGN: Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120). RESULTS: In 69 patients (42 males, 27 females, mean age 44.6±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242-128mg/g (p=0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR≤60ml/min/1.73m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models. CONCLUSIONS: GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes.

Predictors of outcome in a Spanish cohort of patients with Fabry disease on enzyme replacement therapy.

Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT. STUDY DESIGN: Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120). RESULTS: In 69 patients (42 males, 27 females, mean age 44.6±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242-128mg/g (p=0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR≤60ml/min/1.73m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models. CONCLUSIONS: GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes.

Extensive antimicrobial resistance mobilization via multicopy plasmid encapsidation mediated by temperate phages.

OBJECTIVES: To investigate the relevance of multicopy plasmids in antimicrobial resistance and assess their mobilization mediated by phage particles. METHODS: Several databases with complete sequences of plasmids and annotated genes were analysed. The 16S methyltransferase gene armA conferring high-level aminoglycoside resistance was used as a marker in eight different plasmids, from different incompatibility groups, and with differing sizes and plasmid copy numbers. All plasmids were transformed into Escherichia coli bearing one of four different lysogenic phages. Upon induction, encapsidation of armA in phage particles was evaluated using qRT-PCR and Southern blotting. RESULTS: Multicopy plasmids carry a vast set of emerging clinically important antimicrobial resistance genes. However, 60% of these plasmids do not bear mobility (MOB) genes. When carried on these multicopy plasmids, mobilization of a marker gene armA into phage capsids was up to 10000 times more frequent than when it was encoded by a large plasmid with a low copy number. CONCLUSIONS: Multicopy plasmids and phages, two major mobile genetic elements (MGE) in bacteria, represent a novel high-efficiency transmission route of antimicrobial resistance genes that deserves further investigation.

Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis.

BACKGROUND: PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood. OBJECTIVES: The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort. METHODS: Clinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied. RESULTS: At first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died. CONCLUSIONS: PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.

On the robustness of real-time myoelectric control investigations: a multiday Fitts' law approach.

OBJECTIVE: Real-time myoelectric experimental protocol is considered as a means to quantify usability of myoelectric control schemes. While usability should be considered over time to assure clinical robustness, all real-time studies reported thus far are limited to a single session or day and thus the influence of time on real-time performance is still unexplored. In this study, the aim was to develop a novel experimental protocol to quantify the effect of time on real-time performance measures over multiple days using a Fitts' law approach. APPROACH: Four metrics: throughput, completion rate, path efficiency and overshoot, were assessed using three train-test strategies: (i) an artificial neural network (ANN) classifier was trained on data collected from the previous day and tested on present day (BDT) (ii) trained and tested on the same day (WDT) and (iii) trained on all previous days including present day and tested on present day (CDT) in a week-long experimental protocol. MAIN RESULTS: It was found that on average, the completion rate (98.37% ± 1.47%) of CDT was significantly better (P < 0.01) than that of BDT (86.25% ± 3.46%) and WDT (94.22% ± 2.74%). The throughput (0.40 ± 0.03 bits s-1) of CDT was significantly better (P = 0.001) than that of BDT (0.38 ± 0.03 bits s-1). Offline analysis showed a different trend due to the difference in the training strategies. SIGNIFICANCE: Results suggest that increasing the size of the training set over time can be beneficial to assure robust performance of the system over time.

Mid-Term Results of Surgical Treatment of Atrial Fibrillation in Valvular Heart Disease Assesed by Speckle Tracking Echocardiography / Resultados em Médio Prazo do Tratamento da Fibrilação Atrial na Doença Valvular Cardíaca Avaliados por Ecocardiografia com Speckle Tracking

Abstract Background: Atrial fibrillation frequently affects patients with valvular heart disease. Ablation of atrial fibrillation during valvular surgery is an alternative for restoring sinus rhythm. Objectives: This study aimed to evaluate mid-term results of successful atrial fibrillation surgical ablation during valvular heart disease surgery, to explore left atrium post-ablation mechanics and to identify predictors of recurrence. Methods: Fifty-three consecutive candidates were included. Eligibility criteria for ablation included persistent atrial fibrillation <10 years and left atrium diameter < 6.0 cm. Three months after surgery, echocardiogram, 24-hour Holter monitoring and electrocardiograms were performed in all candidates who maintained sinus rhythm (44 patients). Echo-study included left atrial deformation parameters (strain and strain rate), using 2-dimensional speckle-tracking echocardiography. Simultaneously, 30 healthy individuals (controls) were analyzed with the same protocol for left atrial performance. Significance was considered with a P value of < 0.05. Results: After a mean follow up of 17 ± 2 months, 13 new post-operative cases of recurrent atrial fibrillation were identified. A total of 1,245 left atrial segments were analysed. Left atrium was severely dilated in the post-surgery group and, mechanical properties of left atrium did not recover after surgery when compared with normal values. Left atrial volume (≥ 64 mL/m2) was the only independent predictor of atrial fibrillation recurrence (p = 0.03). Conclusions: Left atrial volume was larger in patients with atrial fibrillation recurrence and emerges as the main predictor of recurrences, thereby improving the selection of candidates for this therapy; however, no differences were found regarding myocardial deformation parameters. Despite electrical maintenance of sinus rhythm, left atrium mechanics did not recover after atrial fibrillation ablation performed during valvular heart disease surgery.

Resumo Fundamento: A fibrilação atrial frequentemente afeta pacientes com doenças das valvas cardíacas. A ablação da fibrilação atrial durante a cirurgia das válvulas é uma alternativa para restaurar o ritmo sinusal. Objetivos: Este estudo teve como objetivos avaliar resultados em médio prazo da ablação cirúrgica bem sucedida da FA durante cirurgia para doença valvar, para explorar a mecânica do AE após a ablação e identificar preditores de recorrência. Métodos: Foram incluídos 53 candidatos consecutivos. Os critérios de elegibilidade para ablação foram fibrilação atrial persistente <10 anos e diâmetro do átrio esquerdo < 6 cm. Três meses após a cirurgia, foram realizados ecocardiografia, Holter por 24 horas, e eletrocardiografias em todos os candidatos que mantiveram o ritmo sinusal (44 pacientes). O estudo eco incluiu parâmetros de deformação ao átrio esquerdo (strain e taxa de strain) usando ecocardiografia bidimensional com speckle tracking. Simultaneamente, 30 indivíduos sadios (controles) foram analisados com o mesmo protocolo para o desempenho do átrio esquerdo. Um valor de P < 0,05 foi considerado significativo. Resultados: Após um período médio de acompanhamento de 17 ± 2 meses, 13 novos casos de fibrilação atrial no pós-operatório foram identificados. Um total de 1245 segmentos do átrio esquerdo foi analisado. O grupo pós-cirúrgico apresentou dilatação grave do átrio esquerdo, e as propriedades mecânicas do átrio esquerdo não se recuperaram após a cirurgia quando comparadas com valores normais. O volume do átrio esquerdo (≥ 64 mL/m2) foi o único preditor independente de recorrência de fibrilação atrial (p = 0,03). Conclusões: O volume do átrio esquerdo foi maior nos pacientes com fibrilação atrial recorrente, e desponta como o principal preditor de recorrência, melhorando, assim, a seleção de candidatos para essa terapia. No entanto, não foram encontradas diferenças em relação aos parâmetros de deformação do miocárdio. Apesar da manutenção elétrica do ritmo sinusal, a função mecânica do átrio esquerdo não se recuperou após a ablação da fibrilação atrial realizada durante a cirurgia para doença da valva cardíaca.

Mid-Term Results of Surgical Treatment of Atrial Fibrillation in Valvular Heart Disease Assesed by Speckle Tracking Echocardiography.

BACKGROUND: Atrial fibrillation frequently affects patients with valvular heart disease. Ablation of atrial fibrillation during valvular surgery is an alternative for restoring sinus rhythm. OBJECTIVES: This study aimed to evaluate mid-term results of successful atrial fibrillation surgical ablation during valvular heart disease surgery, to explore left atrium post-ablation mechanics and to identify predictors of recurrence. METHODS: Fifty-three consecutive candidates were included. Eligibility criteria for ablation included persistent atrial fibrillation <10 years and left atrium diameter < 6.0 cm. Three months after surgery, echocardiogram, 24-hour Holter monitoring and electrocardiograms were performed in all candidates who maintained sinus rhythm (44 patients). Echo-study included left atrial deformation parameters (strain and strain rate), using 2-dimensional speckle-tracking echocardiography. Simultaneously, 30 healthy individuals (controls) were analyzed with the same protocol for left atrial performance. Significance was considered with a P value of < 0.05. RESULTS: After a mean follow up of 17 ± 2 months, 13 new post-operative cases of recurrent atrial fibrillation were identified. A total of 1,245 left atrial segments were analysed. Left atrium was severely dilated in the post-surgery group and, mechanical properties of left atrium did not recover after surgery when compared with normal values. Left atrial volume (≥ 64 mL/m2) was the only independent predictor of atrial fibrillation recurrence (p = 0.03). CONCLUSIONS: Left atrial volume was larger in patients with atrial fibrillation recurrence and emerges as the main predictor of recurrences, thereby improving the selection of candidates for this therapy; however, no differences were found regarding myocardial deformation parameters. Despite electrical maintenance of sinus rhythm, left atrium mechanics did not recover after atrial fibrillation ablation performed during valvular heart disease surgery.

Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.

INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited heart disease. Next-generation sequencing (NGS) is the preferred genetic test, but the diagnostic value of screening for minor and candidate genes, and the role of copy number variants (CNVs) deserves further evaluation. METHODS: Three hundred and eighty-seven consecutive unrelated patients with HCM were screened for genetic variants in the 5 most frequent genes (MYBPC3, MYH7, TNNT2, TNNI3 and TPM1) using Sanger sequencing (N = 84) or NGS (N = 303). In the NGS cohort we analyzed 20 additional minor or candidate genes, and applied a proprietary bioinformatics algorithm for detecting CNVs. Additionally, the rate and classification of TTN variants in HCM were compared with 427 patients without structural heart disease. RESULTS: The percentage of patients with pathogenic/likely pathogenic (P/LP) variants in the main genes was 33.3%, without significant differences between the Sanger sequencing and NGS cohorts. The screening for 20 additional genes revealed LP variants in ACTC1, MYL2, MYL3, TNNC1, GLA and PRKAG2 in 12 patients. This approach resulted in more inconclusive tests (36.0% vs. 9.6%, p<0.001), mostly due to variants of unknown significance (VUS) in TTN. The detection rate of rare variants in TTN was not significantly different to that found in the group of patients without structural heart disease. In the NGS cohort, 4 patients (1.3%) had pathogenic CNVs: 2 deletions in MYBPC3 and 2 deletions involving the complete coding region of PLN. CONCLUSIONS: A small percentage of HCM cases without point mutations in the 5 main genes are explained by P/LP variants in minor or candidate genes and CNVs. Screening for variants in TTN in HCM patients drastically increases the number of inconclusive tests, and shows a rate of VUS that is similar to patients without structural heart disease, suggesting that this gene should not be analyzed for clinical purposes in HCM.

Prevalence and molecular epidemiology of imipenem-resistant Pseudomonas aeruginosa carrying metallo-beta-lactamases from two central hospitals in Portugal.

Metallo-beta-lactamases (MBLs) can confer broad-spectrum beta-lactam resistance, including carbapenems. The aim of this work was to document the occurrence of MBLs in 122 imipenem-resistant Pseudomonas aeruginosa isolates collected in two Portuguese central hospitals, to determine their antimicrobial susceptibility, and to observe if there were intra- and interhospital epidemic spread. About 20.5% of these isolates presented blaVIM-2, which was found to be widespread in both hospitals. Clonal diversity was observed within hospitals, and no interhospital spread was observed. Ten of the blaVIM-2-positive isolates (44%), from both hospitals, presented one or two class 1 integrons. Two of those contained a VIM-2 gene, one from each hospital, which is indicative for the possibility of MBL gene transfer. No interhospital spread of integrons was observed. Regular screening and surveillance is needed to prevent spread of this worrisome resistance determinant.

Functional anatomy of aortic regurgitation. Role of transesophageal echocardiography in aortic valve-sparing surgery.

INTRODUCTION AND OBJECTIVES: The aim was to evaluate the usefulness of transesophageal echocardiography (TEE) for the preoperative functional anatomical assessment of patients with aortic regurgitation (AR) to identify those eligible for valve-sparing surgery (VSS). METHODS: We determined the accuracy and diagnostic value of TEE for identifying underlying lesions and mechanisms in 66 patients who underwent surgery for severe AR by comparing TEE findings with those obtained on surgical inspection. The usefulness of TEE for predicting the feasibility of VSS was determined. RESULTS: The overall diagnostic accuracy of TEE was excellent (87%, kappa=0.82), with valve prolapse being the principle cause of discrepancy between the methods (in 23/27 cases; 85%). Three anatomical forms of dilatation of the ascending aorta (AA) were correctly classified (accuracy >88%; kappa 0.83): supratubal aneurysm (19 patients), aortic root aneurysm (4), and annuloaortic ectasia (24). The mechanism underlying AR was identified with an accuracy of 85% (kappa 0.8) and there was a significant association between the type of mechanism identified by TEE and the success of VSS (P< .001): VSS was successful in 73% of patients with dilatation of a functional annulus (i.e. with tethering), but aortic valve replacement was required in 78% with prolapses, 90% with thickened leaflets with restricted movement, and 100% with perforation. There was also a relationship between the type of aneurysm and the technique required for AA replacement (P=.004). CONCLUSIONS: Use of TEE enabled the mechanism underlying AR to be accurately identified. There was a high level of agreement with surgical inspection and the technique was useful for predicting the feasibility of VSS and the surgical procedure for AA replacement.

Anatomía funcional de la insuficiencia aórtica. Papel de la ecocardiografía transesofágica en la cirugía conservadora de válvula aórtica / Functional anatomy of aortic regurgitation. Role of transesophageal echocardiography in aortic valve-sparing surgery

Introducción y objetivos. Intentamos determinar el papel de la ecocardiografía transesofágica (ETE) en la descripción preoperatoria de la anatomía funcional de la insuficiencia aórtica (IAo) para identificar candidatos a cirugía conservadora (CCVAo). Métodos. En 66 pacientes intervenidos de IAo severa se determinan precisión y valores diagnósticos de la ETE en la descripción de lesiones y mecanismos, empleando la observación quirúrgica como referencia. Se valora la utilidad de la ETE para predecir aplicabilidad de técnicas de CCVAo. Resultados. La exactitud diagnóstica general de la ETE es excelente (87%, índice kappa = 0,82); el prolapso presenta la principal discrepancia (23/27 casos; 85%) entre los métodos. Tres formas anatómicas de dilatación de aorta ascendente (AA) fueron correctamente clasificadas (precisión, > 88%; kappa = 0,83): aneurisma de AA supratubular (19), aneurisma de raíz (4) o anuloectasia aórtica (24). La precisión en el diagnóstico del mecanismo fue del 85% (kappa = 0,8) y éste presentó una asociación significativa con el éxito de la CCVAo (p < 0,001) en el 73% de los casos de dilatación de los anillos funcionales (tethering). El 78% de prolapsos, el 90% de movimiento restrictivo de velos engrosados y el 100% de perforaciones requirieron sustitución valvular aórtica. Las formas de aneurisma también se relacionaron con el procedimiento de sustitución de AA (p = 0,004). Conclusiones. La ETE permite una descripción precisa de los mecanismos de la IAo, tiene una elevada tasa de acuerdo con las observaciones quirúrgicas y predice adecuadamente la aplicabilidad de la CCVAo y el procedimiento de sustitución de AA (AU)

Introduction and objectives. The aim was to evaluate the usefulness of transesophageal echocardiography (TEE) for the preoperative functional anatomical assessment of patients with aortic regurgitation (AR) to identify those eligible for valve-sparing surgery (VSS). Methods. We determined the accuracy and diagnostic value of TEE for identifying underlying lesions and mechanisms in 66 patients who underwent surgery for severe AR by comparing TEE findings with those obtained on surgical inspection. The usefulness of TEE for predicting the feasibility of VSS was determined. Results. The overall diagnostic accuracy of TEE was excellent (87%, kappa=0.82), with valve prolapse being the principle cause of discrepancy between the methods (in 23/27 cases; 85%). Three anatomical forms of dilatation of the ascending aorta (AA) were correctly classified (accuracy >88%; kappa 0.83): supratubal aneurysm (19 patients), aortic root aneurysm (4), and annuloaortic ectasia (24). The mechanism underlying AR was identified with an accuracy of 85% (kappa 0.8) and there was a significant association between the type of mechanism identified by TEE and the success of VSS (P < .001): VSS was successful in 73% of patients with dilatation of a functional annulus (i.e. with tethering), but aortic valve replacement was required in 78% with prolapses, 90% with thickened leaflets with restricted movement, and 100% with perforation. There was also a relationship between the type of aneurysm and the technique required for AA replacement (P=.004). Conclusions. Use of TEE enabled the mechanism underlying AR to be accurately identified. There was a high level of agreement with surgical inspection and the technique was useful for predicting the feasibility of VSS and the surgical procedure for AA replacement (AU)