Cardiac magnetic resonance patterns of left ventricular remodeling in patients with severe aortic stenosis referred to surgical aortic valve replacement.

Left ventricular (LV) hypertrophy is a common finding in patients with severe aortic stenosis (AS). Cardiac magnetic resonance (CMR) is the gold-standard technique to evaluate LV remodeling. Our aim was to assess the prevalence and describe the patterns of LV adaptation in AS patients before and after surgical aortic valve replacement (AVR). Prospective study of 130 consecutive patients (71y [IQR 68-77y], 48% men) with severe AS, referred for surgical AVR. Patterns of LV remodeling were assessed by CMR. Besides normal LV ventricular structure, four other patterns were considered: concentric remodeling, concentric hypertrophy, eccentric hypertrophy, and adverse remodeling. At baseline CMR study: mean LV indexed mass: 81.8 ± 26.7 g/m2; mean end-diastolic LV indexed volume: 85.7 ± 23.1 mL/m2 and median geometric remodeling ratio: 0.96 g/mL [IQR 0.82-1.08 g/mL]. LV hypertrophy occurred in 49% of subjects (concentric 44%; eccentric 5%). Both normal LV structure and concentric remodeling had a prevalence of 25% among the cohort; one patient had an adverse remodeling pattern. Asymmetric LV wall thickening was present in 55% of the patients, with predominant septal involvement. AVR was performed in 119 patients. At 3-6 months after AVR, LV remodeling changed to: normal ventricular geometry in 60%, concentric remodeling in 27%, concentric hypertrophy in 10%, eccentric hypertrophy in 3% and adverse remodeling (one patient). Indexes of AS severity, LV systolic and diastolic function and NT-proBNP were significantly different among the distinct patterns of remodeling. Several distinct patterns of LV remodelling beyond concentric hypertrophy occur in patients with classical severe AS. Asymmetric hypertrophy is a common finding and LV response after AVR is diverse.

Histopathological myocardial changes in patients with severe aortic stenosis referred for surgical valve replacement: a cardiac magnetic resonance correlation study.

AIMS: Myocardial fibrosis (MF) takes part in left ventricular (LV) remodelling in patients with aortic stenosis (AS), driving the transition from hypertrophy to heart failure. The structural changes that occur in this transition are not fully enlightened. The aim of this study was to describe histopathological changes at endomyocardial biopsy (EMB) in patients with severe AS referred to surgical aortic valve replacement (AVR) and to correlate them with LV tissue characterization from pre-operative cardiac magnetic resonance (CMR). METHODS AND RESULTS: One-hundred fifty-eight patients [73 (68-77) years, 50% women] were referred for surgical AVR because of severe symptomatic AS, with pre-operative CMR (n = 143) with late gadolinium enhancement (LGE), T1, T2 mapping, and extracellular volume fraction (ECV) quantification. Intra-operative septal EMB was obtained in 129 patients. MF was assessed through Masson's Trichrome histochemistry. Immunohistochemistry was performed for both inflammatory cells and extracellular matrix (ECM) characterization (Type I Collagen, Fibronectin, Tenascin C). Non-ischaemic LGE was present in 106 patients (67.1%) [median fraction: 5.0% (2.0-9.7)]. Native T1 was above normal [1053 ms (1024-1071)] and T2 within the normal range [39.3 ms (37.3-42.0)]. Median MF was 11.9% (6.54-19.97), with predominant type I collagen perivascular distribution (95.3%). Sub-endocardial cardiomyocyte ischaemic-like changes were identified in 45% of EMB. There was no inflammation, despite ECM remodelling expression. MF quantification at EMB was correlated with LGE mass (P = 0.008) but not with global ECV (P = 0.125). CONCLUSION: Patients with severe symptomatic AS referred for surgical AVR have unspecific histological myocardial changes, including signs of cardiomyocyte ischaemic insult. ECM remodelling is ongoing, with MF heterogeneity. These features may be recognized by comprehensive CMR protocols. However, no single CMR parameter captures the burden of MF and histological myocardial changes in this setting.

Is myocardial fibrosis appropriately assessed by calibrated and 2D strain derived integrated backscatter?

AIMS: Increased collagen content of the myocardium modifies tissue reflectivity and integrated backscatter (IBS) indexes are suggested as markers of myocardial fibrosis (MF). We sought to assess the correlation between calibrated (c) IBS and bidimensional (2D) strain derived IBS with left ventricular (LV) MF in patients with severe aortic stenosis (AS). METHODS AND RESULTS: We made a prospective observational cohort study including 157 patients with severe AS referred for surgical aortic valve replacement (AVR), with complete preoperative transthoracic echocardiography, cardiac magnetic resonance (CMR) and endomyocardial biopsy (EMB) obtained from the anterior basal septum at the time of surgery. Two groups of 30 patients were specifically evaluated, with and without late gadolinium enhancement (LGE) at CMR. IBS was obtained at QRS peak from both parasternal long axis (PLAX) and apical-three-chamber (AP3C) views and measured in decibels (dB). Whole-cardiac cycle IBS at basal anterior septum was obtained from 2D longitudinal strain. Correlation analysis of reflectivity indexes was performed with global and segmental (anterior basal septum) values of native T1 and extracellular volume (ECV), and EMB collagen volume fraction (CVF) (Masson´s Trichrome). IBS values were compared in both group of patients (LGE + vs. LGE -). 60 patients (74 [36-74] years, 45% male) with high gradient (mean gradient: 63 ± 20mmHg), normal flow (45 ± 10mL/m2) AS and preserved left ventricular ejection fraction (60 ± 9%) were included. Basal septum cIBS was - 17.45 (-31.2-10.95) and - 9.17 ± 9.45dB from PLAX and A3C views, respectively. No significant correlations were found between IBS and both non-invasive CMR tissue characterization and CVF: median MF of 9.7(2.1-79.9)%. Acoustic indexes were not significantly different according to the presence of pre-operative LGE. CONCLUSION: In this group of patients with classical severe AS, IBS reflectivity indexes are of no added value to discriminate the presence of MF.

The influence of comorbidities on the prognosis after an acute heart failure decompensation and differences according to ejection fraction: Results from the EAHFE and RICA registries.

OBJECTIVE: The role of comorbidities in heart failure (HF) outcome has been previously investigated, although mostly individually. We investigated the individual effect of 13 comorbidities on HF prognosis and looked for differences according to left-ventricular ejection fraction (LVEF), classified as reduced (HFrEF), mildly-reduced (HFmrEF) and preserved (HFpEF). METHODS: We included patients from the EAHFE and RICA registries and analysed the following comorbidities: hypertension, dyslipidaemia, diabetes mellitus (DM), atrial fibrillation (AF), coronary artery disease (CAD), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), heart valve disease (HVD), cerebrovascular disease (CVD), neoplasia, peripheral artery disease (PAD), dementia and liver cirrhosis (LC). Association of each comorbidity with all-cause mortality was assessed by an adjusted Cox regression analysis that included the 13 comorbidities, age, sex, Barthel index, New York Heart Association functional class and LVEF and expressed as adjusted Hazard Ratios (HR) with 95% confidence intervals (95%CI). RESULTS: We analysed 8,336 patients (82 years-old; 53% women; 66% with HFpEF). Mean follow-up was 1.0 years. Respect to HFrEF, mortality was lower in HFmrEF (HR:0.74;0.64-0.86) and HFpEF (HR:0.75;0.68-0.84). Considering patients all together, eight comorbidities were associated with mortality: LC (HR:1.85;1.42-2.42), HVD (HR:1.63;1.48-1.80), CKD (HR:1.39;1.28-1.52), PAD (HR:1.37;1.21-1.54), neoplasia (HR:1.29;1.15-1.44), DM (HR:1.26;1.15-1.37), dementia (HR:1.17;1.01-1.36) and COPD (HR:1.17;1.06-1.29). Associations were similar in the three LVEF subgroups, with LC, HVD, CKD and DM remaining significant in the three subgroups. CONCLUSION: HF comorbidities are associated differently with mortality, LC being the most associated with mortality. For some comorbidities, this association can be significantly different according to the LVEF.

LGE prevalence and patterns in severe aortic stenosis: When "junctional" means the same.

BACKGROUND: Left ventricular (LV) remodeling in severe aortic valve stenosis (AS) is a complex process that goes beyond hypertrophic response. Reparative/replacement fibrosis is considered irreversible and has recognized value in both risk stratification and prognosis. Currently, cardiac magnetic resonance (CMR) is the gold-standard imaging technique for fibrosis identification through late gadolinium enhancement (LGE) assessment. However, its prevalence and distribution are quite variable among series. Our goal was to assess LGE prevalence and patterns in severe AS. METHODOLOGY: Single-center prospective cohort of 140 patients with severe symptomatic high-gradient AS (mean age 72 ± 8 years; mean valvular transaortic gradient 61 ± 18 mmHg; mean LV ejection fraction by echocardiogram 58 ± 9%) undergoing surgical aortic valve replacement. Those with previous myocardial infarction and/or non-ischemic cardiomyopathy were excluded. All patients performed 1.5 T LGE-CMR prior to surgery. RESULTS: Overall, 103 patients (74%) had non-ischemic LGE (median LGE mass 2.8 g [IQR 0.0-7.8] g), many of them with combined mid-wall and junctional enhancement pattern (36%). LGE was most frequently observed in the mid-basal segments of the interventricular septum. Seventy-four patients (53%) had non-exclusively junctional LGE. Contrary to those with junctional enhancement, patients with non-exclusively junctional LGE had higher LV volumes/mass, worse LV ejection fraction and worse global longitudinal strain. CONCLUSION: Among patients with severe, symptomatic, high-gradient AS, LGE is frequent, primarily affecting the mid-basal interventricular septum. Contrary to junctional LGE, the presence of non-junctional LGE seems to correlate with adverse markers of LV remodeling.

Prevalence and significance of relative apical sparing in aortic stenosis: insights from an echo and cardiovascular magnetic resonance study of patients referred for surgical aortic valve replacement.

AIMS: This study aims to assess the prevalence of relative apical sparing pattern (RASP) in patients with severe symptomatic aortic stenosis (AS), referred for surgical aortic valve replacement (AVR), to evaluate its significance, possible relation to amyloid deposition, and persistence after surgery. METHODS AND RESULTS: Prospective study of 150 consecutive patients [age 73 (interquartile range: 68-77), 51% women], with severe symptomatic AS referred to surgical AVR. All patients underwent cardiac magnetic resonance (CMR) before surgery. RASP was defined by [average apical longitudinal strain (LS)/(average basal LS + average mid LS)] > 1 by echocardiography. AVR was performed in 119 (79.3%) patients. Both Congo red and sodium sulphate-Alcian blue (SAB) stain were used to exclude amyloid on septal myocardial biopsy. LV remodelling and tissue characterization parameters were compared in patients with and without RASP. Deformation pattern was re-assessed at 3-6 months after AVR.RASP was present in 23 patients (15.3%). There was no suspicion of amyloid at pre-operative CMR [native T1 value 1053 ms (1025-1076 ms); extracellular volume (ECV) 28% (25-30%)]. None of the patients had amyloid deposition at histopathology. Patients with RASP had significantly higher pre-operative LV mass and increased septal wall thickness. They also had higher N-terminal pro b-type natriuretic peptide (NT-proBNP) levels [1564 (766-3318) vs. 548 (221-1440) pg/mL, P = 0.010], lower LV ejection fraction (53.7 ± 10.5 vs. 60.5 ± 10.2%, P = 0.005), and higher absolute late gadolinium enhancement (LGE) mass [9.7 (5.4-14.1) vs. 4.8 (1.9-8.6) g, P = 0.016] at CMR. Follow-up evaluation after AVR revealed RASP disappearance in all except two of the patients. CONCLUSION: RASP is not specific of cardiac amyloidosis. It may also be found in severe symptomatic AS without amyloidosis, reflecting advanced LV disease, being mostly reversible after surgery.

Factors associated with in-hospital mortality and adverse outcomes during the vulnerable post-discharge phase after the first episode of acute heart failure: results of the NOVICA-2 study.

OBJECTIVE: To identify patients at risk of in-hospital mortality and adverse outcomes during the vulnerable post-discharge period after the first acute heart failure episode (de novo AHF) attended at the emergency department. METHODS: This is a secondary review of de novo AHF patients included in the prospective, multicentre EAHFE (Epidemiology of Acute Heart Failure in Emergency Department) Registry. We included consecutive patients with de novo AHF, for whom 29 independent variables were recorded. The outcomes were in-hospital all-cause mortality and all-cause mortality and readmission due to AHF within 90 days post-discharge. A follow-up check was made by reviewing the hospital medical records and/or by phone. RESULTS: We included 3422 patients. The mean age was 80 years, 52.1% were women. The in-hospital mortality was 6.9% and was independently associated with dementia (OR = 2.25, 95% CI = 1.62-3.14), active neoplasia (1.97, 1.41-2.76), functional dependence (1.58, 1.02-2.43), chronic treatment with beta-blockers (0.62, 0.44-0.86) and severity of decompensation (6.38, 2.86-14.26 for high-/very high-risk patients). The 90-day post-discharge combined endpoint was observed in 19.3% of patients and was independently associated with hypertension (HR = 1.40, 1.11-1.76), chronic renal insufficiency (1.23, 1.01-1.49), heart valve disease (1.24, 1.01-1.51), chronic obstructive pulmonary disease (1.22, 1.01-1.48), NYHA 3-4 at baseline (1.40, 1.12-1.74) and severity of decompensation (1.23, 1.01-1.50; and 1.64, 1.20-2.25; for intermediate and high-/very high-risk patients, respectively), with different risk factors for 90-day post-discharge mortality or rehospitalisation. CONCLUSIONS: The severity of decompensation and some baseline characteristics identified de novo AHF patients at increased risk of developing adverse outcomes during hospitalisation and the vulnerable post-discharge phase, without significant differences in these risk factors according to patient age at de novo AHF presentation.

Influence of previous coronary artery bypass grafting in the difficulty of acute coronary syndrome diagnosis.

OBJECTIVES: To investigate whether the diagnosis of acute coronary syndrome (ACS) in coronary artery bypass grafting (CABG) patients with chest pain (CP) is more difficult based on the initial clinical and electrocardiogram (ECG) findings. METHODS: We included consecutive CP patients attended at a single emergency department (ED) during a 10-year period. CABG status and the final diagnosis of ACS were considered as stated in the ED discharge report. We evaluated the frequency of 21 CP characteristics (CPC) and four ECG signatures, their individual and collective association with ACS, and ED length of stay (LOS) in CABG and non-CABG patients. RESULTS: We included 34 429 patients [median age: 61 years; female: 41.8%; CABG: 2204 patients (6.4%)], and ACS was diagnosed in 6727 (19.5%; CABG/non-CABG 37.2%/18.3%; P < 0.001). CABG patients more frequently had CPC and ECG findings typically associated with ACS, but their final association with ACS was weaker than in non-CABG patients (only significant after adjustment for attendant diaphoresis, throat irradiation, ST-segment elevation and T-wave inversion). The collective discriminative capacity was significantly lower in CABG patients (area under the curve 0.710 vs. 0.793; P < 0.001), even after adjustment (0.708 vs. 0.790; P < 0.001). ED LOS was longer for CABG patients, overall (P < 0.001) and for patients diagnosed with ACS (P = 0.008) and non-ACS (P < 0.001), but these differences disappeared after adjustment. CONCLUSION: CABG substantially reduces the diagnostic performance of CPC and ECG findings to suggest ACS. A longer LOS in the ED in CABG patients is more related to their baseline characteristics than to CABG itself.

Biventricular arrhythmogenic cardiomyopathy: a new paradigm? / Cardiomiopatia arritmogênica biventricular: um novo paradigma?

Arrhythmogenic right ventricular dysplasia is a classic form of chronic myocardial disease with a broad phenotypical spectrum. We report an atypical case of a patient with biventricular arrhythmogenic cardiomyopathy. Although the current diagnosis criteria are the most widely accepted ones, they focus solely on the right ventricular phenotype. The use of late gadolinium enhancement in cardiac magnetic resonance in this patient was essential for the diagnosis and assessment of the left ventricular involvement extent. This tool allows a broader use of current diagnosis criteria for this disease

Preditores de fibrilação atrial de novo em unidade de cuidados intensivos não cardíaca / Predictors of de novo atrial fibrillation in a non-cardiac intensive care unit

RESUMO Objetivo: Avaliar quais os preditores de fibrilação atrial de novo em doentes de uma unidade de cuidados intensivos não cardíaca. Métodos: Foram analisados 418 doentes internados entre janeiro e setembro de 2016 em uma unidade de cuidados intensivos não cardíaca. Registaram-se as características clínicas, as intervenções efetuadas e os marcadores bioquímicos durante a internação. Avaliaram-se ainda a mortalidade hospitalar e o tempo de internação hospitalar e na unidade de cuidados intensivos. Resultados: Foram incluídos 310 doentes, com média de idades de 61,0 ± 18,3 anos, 49,4% do sexo masculino, 23,5% com fibrilação atrial de novo. O modelo multivariável identificou acidente vascular cerebral prévio (OR de 10,09; p = 0,016) e valores aumentados de proBNP (OR de 1,28 por cada aumento em 1.000pg/mL; p = 0,004) como preditores independentes de fibrilação atrial de novo. A análise por curva Característica de Operação do Receptor do proBNP para predição de fibrilação atrial de novo revelou área sob a curva de 0,816 (p < 0,001), com sensibilidade de 65,2% e especificidade de 82% para proBNP > 5.666pg/mL. Não se verificaram diferenças na mortalidade (p = 0,370), porém a duração da internação hospitalar (p = 0,002) e na unidade de cuidados intensivos (p = 0,031) foi superior nos doentes com fibrilação atrial de novo. Conclusões: História de acidente vascular cerebral prévio e proBNP elevado em internação constituíram preditores independentes de fibrilação atrial de novo na unidade de cuidados intensivos polivalente. O proBNP pode constituir ferramenta útil, de fácil e rápido acesso na estratificação do risco de fibrilação atrial.

ABSTRACT Objective: To assess the predictors of de novo atrial fibrillation in patients in a non-cardiac intensive care unit. Methods: A total of 418 hospitalized patients were analyzed between January and September 2016 in a non-cardiac intensive care unit. Clinical characteristics, interventions, and biochemical markers were recorded during hospitalization. In-hospital mortality and length of hospital stay in the intensive care unit were also evaluated. Results: A total of 310 patients were included. The mean age of the patients was 61.0 ± 18.3 years, 49.4% were male, and 23.5% presented de novo atrial fibrillation. The multivariate model identified previous stroke (OR = 10.09; p = 0.016) and elevated levels of pro-B type natriuretic peptide (proBNP, OR = 1.28 for each 1,000pg/mL increment; p = 0.004) as independent predictors of de novo atrial fibrillation. Analysis of the proBNP receiver operating characteristic curve for prediction of de novo atrial fibrillation revealed an area under the curve of 0.816 (p < 0.001), with a sensitivity of 65.2% and a specificity of 82% for proBNP > 5,666pg/mL. There were no differences in mortality (p = 0.370), but the lengths of hospital stay (p = 0.002) and stay in the intensive care unit (p = 0.031) were higher in patients with de novo atrial fibrillation. Conclusions: A history of previous stroke and elevated proBNP during hospitalization were independent predictors of de novo atrial fibrillation in the polyvalent intensive care unit. The proBNP is a useful and easy- and quick-access tool in the stratification of atrial fibrillation risk.

Impact of geriatric assessment variables on 30-day mortality among older patients with acute heart failure. / Impacto de las variables geriátricas en la mortalidad a 30 días de los ancianos atendidos por insuficiencia cardiaca aguda?

OBJETIVE: To study the impact of geriatric assessment variables on 30-day mortality among older patients with acute heart failure (AHF). METHODS: Retrospective analysis of cases in the OAK Registry (Older Acute Heart Failure Key Data), a prospectively compiled database of consecutive patients aged 65 years or older treated for AHF in 3 Spanish emergency departments over a 4-month period (November-December 2011 and January-February 2014). The patients underwent a geriatric assessment adapted for emergency department use on weekdays between 8 AM and 10 PM. Demographic, clinical, laboratory, and geriatric assessment variables were recorded. The geriatric variables were concurrent diseases; polypharmacy; frailty; functional, social, and cognitive status at baseline; results of screening for confusional state, cognitive impairment, and depression; and nutritional status. The primary outcome was all-cause mortality at 30 days. RESULTS: We included 565 patients with a mean (SD) age of 83 (7.1) years; 346 (61.6%) were women. Sixty-five (11.5%) died within 30 days. Independent factors associated with 30-day mortality were acute confusional state (adjusted odds ratio [aOR], 2.2; 95% CI, 1.0­4.8; P=.04), acute illness (aOR, 1.8; 95% CI, 0.9­3.4; P=.05), loss of appetite in the past 3 months (aOR, 1.8; 95% CI, 1.0­3.4; P=.04), frailty (aOR, 2.0, 95% CI, 1.0­4.1; P=.05), and severe disability (aOR, 4.4; 95% CI, 1.9­11.4; P=.01). CONCLUSIONS: Certain geriatric variables should be considered when assessing short-term risk in older patients with AHF.

OBJETIVOS: Estudiar el impacto de las variables geriátricas en la mortalidad a 30 días entre los ancianos con insuficiencia cardiaca aguda (ICA). MÉTODO: Análisis retrospectivo del registro Older Acute heart failure Key data (OAK) que incluye prospectivamente a pacientes consecutivos 65 años con ICA en 3 servicios de urgencias españoles durante 4 meses (noviembre-diciembre 2011 y enero-febrero 2014). Se realizó una valoración geriátrica adaptada a urgencias durante los días laborales de 8 am a 10 pm. Se recogieron variables demográficas, clínicas, analíticas y geriátricas (comorbilidad, polifarmacia, fragilidad, situación basal funcional, cognitiva y social, despistaje de síndrome confusional, deterioro cognitivo y depresión, y situación nutricional). La variable de resultado fue la mortalidad por cualquier causa a los 30 días. RESULTADOS: Se incluyeron 565 pacientes con edad media 83 años (DE 7,1), 346 mujeres (61,6%). Sesenta y cinco sujetos (11,5%) fallecieron a los 30 días. La presencia de síndrome confusional agudo (OR ajustada = 2,2; IC95% 1,0-4,8; p = 0,04), de enfermedad aguda (OR ajustada = 1,8; IC95% 0,9-3,4; p = 0,05) o pérdida de apetito (OR ajustada = 1,8; IC95% 1-3,4; p = 0,04) en los últimos 3 meses, y de fragilidad (OR ajustada = 2,0; IC95% 1,0-4,1; p = 0,05) o dependencia funcional grave (OR ajustada = 4,4; IC95% 1,9-11,4; p = 0,01) fueron factores independientes asociados con mortalidad a los 30 días. CONCLUSIONES: Existen ciertas variables geriátricas que debieran contemplarse en la estratificación de riesgo a corto plazo de los pacientes ancianos con ICA.

Surgical pathology of subaortic septal myectomy: histology skips over clinical diagnosis.

BACKGROUND: Subaortic septal myectomy is usually performed to mitigate obstruction in patients with the obstructive form of hypertrophic cardiomyopathy (HCM) or in those with congenital subaortic stenosis. Moreover, it is combined with aortic valve replacement in patients with severe aortic valve stenosis (SAS) and asymmetrical septal hypertrophy causing concomitant left ventricular outflow tract obstruction. When both conditions coexist, it is conceptually difficult to identify a cardiomyopathy beyond an adaptive myocardial hypertrophy, strictly related to pressure overload. Myectomy histopathology might be useful to enlighten the cause of the obstruction and establish the diagnosis. AIM: The aim was to describe the pathological findings of surgical septal myectomy specimens obtained from a group of patients with diverse clinical diagnosis, including HCM, severe aortic stenosis, and asymmetrical septal hypertrophy. METHODS: This was a retrospective study of 56 patients undergoing septal myectomy along a 10-year period at a tertiary cardiac surgical center. Clinical, interventional, and anatomopathological findings between patients with and without a preoperative diagnosis of HCM were analyzed and compared. RESULTS: Mean age at intervention was 67.5±20.5 years; 37 (66.1%) were female Preoperative diagnosis of sarcomeric obstructive HCM was assumed in 23 (41.1%) patients. All the other patients (58.9%) were referred for surgery with preoperative diagnosis of asymmetric septal hypertrophy, mainly in the context of severe aortic stenosis (24 patients). Twenty-seven (48.2%) patients had a greater than 30 mmHg intraventricular gradient at rest. Patients with presumed HCM were significantly younger (56.5±15.8 vs. 70.2±13.3 years, P<.001), had higher prevalence of significant intraventricular obstruction at rest [20 (87.0%) vs. 8 (34.8%), P<.001], and more frequently had moderate or severe mitral regurgitation [9 (39.1%) vs. 5(15.1%), P=.043]. All patients with aortic valve stenosis underwent both aortic valve replacement and septal myectomy. Twelve (52.1%) of the patients with obstructive HCM had isolated septal myectomy, while in the remaining 11, the procedure was combined with intervention on the mitral valve. Histopathological final diagnosis was of nonspecific reactive myocardial hypertrophy in all but 4 (92.2%) patients. In those, 2 (3.6%) had the final diagnosis of HCM and 2 (3.6%) the diagnosis of congenital subaortic membranous stenosis with reactive myocardial hypertrophy. Different grades of subendocardial fibroelastosis and myocardial fibrosis, mainly interstitial, were present [27 (48.2%) and 18 (32%) patients, respectively]. When microscopic data were compared between patients with or without a preoperative clinical diagnosis of HCM, no significant differences were found. CONCLUSION: In patients submitted to surgical septal myectomy, histology was mostly indistinctive among different clinical entities. Since different myocardial hypertrophy etiologies may share similar pathological expression, there is a need for detailed clinical assessment when trying to define the best strategy for clinical management.

[Diabetes Screening in Patients with Macrovascular Coronary Disease: Are the New European Guidelines a Step Backwards?] / Rastreio da Diabetes em Doentes com Doença Macrovascular Coronária: As Novas Guidelines Europeias são um Retrocesso?

BACKGROUND: The new European guidelines on diabetes mellitus and cardiovascular diseases propose that the FINnish Diabetes RIsk SCore should be used to evaluate the risk of diabetes mellitus and that diabetes mellitus screening in coronary artery disease patients should be based on fasting glucose and HbA1c. The 2 hour oral glucose tolerance test, recommended for all pts in the previous guidelines, is now only recommended for 'inconclusive' cases. We aimed to evaluate this new strategy. MATERIAL AND METHODS: Fasting glucose, HbA1c and glucose tolerance test (75 g, 2h) were prospectively evaluated in a consecutive group of pts with coronary artery disease. ADA criteria (both glucose tolerance test and HbA1c) were used to define diabetes mellitus and pre-diabetes mellitus. Diabetes mellitus risk was evaluated according to the FINnish Diabetes RIsk SCore. RESULTS: A total of 135 patients were included (mean age 62.3 +/- 13.1 years, 99 males). Glucose tolerance test and HbA1c together diagnosed 18 (13.3%) new cases of diabetes mellitus and 77 (57.0%) patients with pre-diabetes mellitus. Fasting glucose + HbA1c (guidelines strategy) identified 12/18 patients with diabetes mellitus (Sens 66.7%; negative predictive value 95.1%; Kappa 0.78; p < 0.0001) and 83/95 patients with glucose anomalies (pre- diabetes mellitus + diabetes mellitus) (Sens 87.4%; negative predictive value 76.9%). Performing glucose tolerance test in the 29 patients with an elevated FINnish Diabetes RIsk SCore would allow identifying 15/18 patients with diabetes mellitus (Sens 83.3%; negative predictive value 97.5%; Kappa 0.85; p < 0.0001) and 86/95 patients with glucose anomalies (Sens 90.5%; negative predictive value 81.6%). DISCUSSION: Although this strategy improved the screening accuracy, one in each six patients with diabetes mellitus would still remain undiagnosed, as compared to measuring HbA1c and performing an glucose tolerance test in all patients. CONCLUSION: Using the FINnish Diabetes RIsk SCore to select candidates to additional glucose tolerance test improves the accuracy for identifying diabetic patients, as compared with fasting glucose + HbA1c alone. However, 1/6 patients diabetes mellitus is still left undiagnosed with this strategy proposed by the current guidelines.

Introdução: As novas recomendações europeias de diabetes mellitus tipo 2 e doença cardiovascular sugerem que o risco de diabetes mellitus tipo 2 deve ser avaliado através do score de risco FINnish Diabetes RIsk SCore e que o rastreio de diabetes mellitus tipo 2 na população com doença arterial coronária deve ser efetuado apenas com a glicemia plasmática em jejum e a HbA1, remetendo a prova de tolerância oral à glicose para os casos 'inconclusivos'. Pretendemos avaliar os resultados desta estratégia, que difere da previamente defendida nas guidelines. Material e Métodos: A glicemia plasmática em jejum, HbA1c e a prova de tolerância oral à glicose (75 g, 2 horas) foram avaliadas prospectivamente num grupo de doentes consecutivos submetidos a intervenção coronária percutânea, sendo usada a classificação da ADA para pré-diabetes mellitus tipo 2 e diabetes mellitus tipo 2. O risco de diabetes foi avaliado de acordo com o FINnish Diabetes RIsk SCore. Resultados: Foram incluídos 135 doentes (idade média 62,3 +/- 13,1 anos; 99 homens). Usando a prova de tolerância oral à glicose e a HbA1c, foram diagnosticados 18 (13,3%) novos casos de diabetes mellitus tipo 2 e 77 (57,0%) casos de pré-diabetes mellitus tipo 2. A glicemia plasmática em jejum + HbA1c identificou 12/18 doentes com diabetes mellitus tipo 2 (Sens 66,7%; valor preditivo negativo 95,1%; Kappa 0,78; p < 0,0001) e 83 do total (pré-diabetes mellitus tipo 2/ diabetes mellitus tipo 2) de 95 doentes com distúrbios da glucose (Sens 87,4%; valor preditivo negativo 76,9%). Realizar adicionalmente prova de tolerância oral à glicose nos 29 doentes com um FINnish Diabetes RIsk SCore elevado permitiu diagnosticar 15/18 doentes com diabetes mellitus (Sens 83,3%; valor preditivo negativo 97,5%; Kappa 0,85; p < 0,0001) e 86/95 dos doentes com distúrbios da glucose (Sens 90,5%; valor preditivo negativo 81,6%). Discussão: Apesar da melhoria diagnóstica, um em cada seis doentes com diabetes mellitus tipo 2 não seria diagnosticado por esta estratégia. Conclusão: A utilização do FINnish Diabetes RIsk SCore como forma de selecionar os doentes candidatos a rastreio com prova de tolerância oral à glicose melhora a capacidade diagnóstica, quando comparada com a simples avaliação da glicemia plasmática em jejum e da HbA1c. No entanto, um em cada seis doentes com diabetes mellitus tipo 2 não é identificado com esta metodologia.

Exploring Binding Mechanisms in Nuclear Hormone Receptors by Monte Carlo and X-ray-derived Motions.

In this study, we performed an extensive exploration of the ligand entry mechanism for members of the steroid nuclear hormone receptor family (androgen receptor, estrogen receptor α, glucocorticoid receptor, mineralocorticoid receptor, and progesterone receptor) and their endogenous ligands. The exploration revealed a shared entry path through the helix 3, 7, and 11 regions. Examination of the x-ray structures of the receptor-ligand complexes further showed two distinct folds of the helix 6-7 region, classified as "open" and "closed", which could potentially affect ligand binding. To improve sampling of the helix 6-7 loop, we incorporated motion modes based on principal component analysis of existing crystal structures of the receptors and applied them to the protein-ligand sampling. A detailed comparison with the anisotropic network model (an elastic network model) highlights the importance of flexibility in the entrance region. While the binding (interaction) energy of individual simulations can be used to score different ligands, extensive sampling further allows us to predict absolute binding free energies and analyze reaction kinetics using Markov state models and Perron-cluster cluster analysis, respectively. The predicted relative binding free energies for three ligands binding to the progesterone receptor are in very good agreement with experimental results and the Perron-cluster cluster analysis highlighted the importance of a peripheral binding site. Our analysis revealed that the flexibility of the helix 3, 7, and 11 regions represents the most important factor for ligand binding. Furthermore, the hydrophobicity of the ligand influences the transition between the peripheral and the active binding site.

Nucleoside inhibitors of tick-borne encephalitis virus.

Tick-borne encephalitis virus (TBEV) is a leading cause of human neuroinfections in Europe and Northeast Asia. There are no antiviral therapies for treating TBEV infection. A series of nucleoside analogues was tested for the ability to inhibit the replication of TBEV in porcine kidney cells and human neuroblastoma cells. The interactions of three nucleoside analogues with viral polymerase were simulated using advanced computational methods. The nucleoside analogues 7-deaza-2'-C-methyladenosine (7-deaza-2'-CMA), 2'-C-methyladenosine (2'-CMA), and 2'-C-methylcytidine (2'-CMC) inhibited TBEV replication. These compounds showed dose-dependent inhibition of TBEV-induced cytopathic effects, TBEV replication (50% effective concentrations [EC50]of 5.1 ± 0.4 µM for 7-deaza-2'-CMA, 7.1 ± 1.2 µM for 2'-CMA, and 14.2 ± 1.9 µM for 2'-CMC) and viral antigen production. Notably, 2'-CMC was relatively cytotoxic to porcine kidney cells (50% cytotoxic concentration [CC50] of ∼50 µM). The anti-TBEV effect of 2'-CMA in cell culture diminished gradually after day 3 posttreatment. 7-Deaza-2'-CMA showed no detectable cellular toxicity (CC50 > 50 µM), and the antiviral effect in culture was stable for >6 days posttreatment. Computational molecular analyses revealed that compared to the other two compounds, 7-deaza-2'-CMA formed a large cluster near the active site of the TBEV polymerase. High antiviral activity and low cytotoxicity suggest that 7-deaza-2'-CMA is a promising candidate for further investigation as a potential therapeutic agent in treating TBEV infection.

Síndrome de Smith-Lemli-Opitz e hipotiroidismo: el primer caso venezolano / Smith-Lemli-Opitz syndrome and hypothyroidism: the first Venezuelan case

El síndrome de Smith-Lemli-Opitz (SSLO) es un desorden metabólico autosómico recesivo debido a la síntesis anormal de colesterol y fue descrito por primera vez por Smith, Lemli y Opitz en 1964. Muchos casos de SSLO han sido descritos desde entonces, siendo reconocido como un síndrome malformativo relativamente común. Los individuos afectados tienen dismorfismo, microcefalia, múltiples malformaciones congénitas, retraso mental, agresividad e hiperactividad. La severidad de los defectos físicos se correlaciona con la severidad de la deficiencia de colesterol, la cual es causada por la baja actividad de la 7-dehidrocolesterol reductasa, enzima responsable de la conversión de 7-dehidrocolesterol a colesterol. La ocurrencia de hipotiroidismo en asociación con SSLO es muy inusual. Este constituye el primer caso venezolano en el que se asocian ambas patologías.

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive metabolic disorder due to an abnormal cholesterol synthesis. It was first described by Smith, Lemli and Opitz in 1964. Many cases of SLOS have been described since then, leading to the recognition as a relatively common malformation syndrome. Affected individuals have dysmorphism, microcephaly, multiple congenital malformations, mental retardation, aggressiveness and hyperactivity. The severity of physical defects correlates with the severity of the cholesterol deficiency, which is caused by an abnormally low activity of 7-dehydrocholesterol reductase, the enzyme responsible for conversion of 7-dehydrocholesterol to cholesterol. The occurrence of hypothyroidism in association with SLOS is very unusual. We describe the first Venezuelan case in which both anomalies are associated.