Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths.

AIMS: Wild-type transthyretin amyloidosis (ATTRwt) is mostly considered a disease predominantly of elderly male, characterized by concentric LV hypertrophy, preserved LVEF, and low QRS voltages. We sought to describe the characteristics of a large cohort of ATTRwt patients to better define the disease. METHODS AND RESULTS: Clinical findings of consecutive ATTRwt patients diagnosed at 2 centres were reviewed. ATTRwt was diagnosed histologically or non-invasively (LV hypertrophy ≥12 mm, intense cardiac uptake at 99mTc-DPD scintigraphy and AL exclusion). Mutations in TTR were excluded in all cases. The study cohort comprised 108 patients (78.6 ± 8 years); 67 (62%) diagnosed invasively and 41 (38%) non-invasively. Twenty patients (19%) were females. An asymmetric hypertrophy pattern was observed in 25 (23%) patients. Mean LVEF was 52 ± 14%, with 39 patients (37%) showing a LVEF < 50%. Atrial fibrillation (56%) and a pseudo-infarct pattern (63%) were the commonest ECG findings. Only 22 patients fulfilled QRS low-voltage criteria while 10 showed LV hypertrophy on ECG. Although heart failure was the most frequent profile leading to diagnosis (68%), 7% of individuals presented with atrioventricular block and 11% were diagnosed incidentally. Almost one third (35; 32%) were previously misdiagnosed. CONCLUSION: The clinical spectrum of ATTRwt is heterogeneous and differs from the classic phenotype: women are affected in a significant proportion; asymmetric LV hypertrophy and impaired LVEF are not rare and only a minority have low QRS voltages. Clinicians should be aware of the broad clinical spectrum of ATTRwt to correctly identify an entity for which a number of disease-modifying treatments are under investigation.

Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome with multiple underlying causes. Wild-type transthyretin (TTR) amyloidosis (ATTRwt) is an underdiagnosed cause of HFpEF that might benefit from new specific treatments. ATTRwt can be diagnosed non-invasively by (99m)Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-DPD) scintigraphy. We sought to determine the prevalence of ATTRwt among elderly patients admitted due to HFpEF. METHODS AND RESULTS: We prospectively screened all consecutive patients ≥60 years old admitted due to HFpEF [left ventricular (LV) ejection fraction ≥50%] with LV hypertrophy (≥12 mm). All eligible patients were offered a (99m)Tc-DPD scintigraphy. The study included 120 HFpEF patients (59% women, 82 ± 8 years). A total of 16 patients (13.3%; 95% confidence interval: 7.2-19.5) showed a moderate-to-severe uptake on the (99m)Tc-DPD scintigraphy. All patients with a positive scan underwent genetic testing of the TTR gene, and no mutations were found. An endomyocardial biopsy was performed in four patients, confirming ATTRwt in all cases. There were no differences in age, gender, hypertension, diabetes, coronary artery disease, or atrial fibrillation between ATTRwt patients and patients with other HFpEF forms. Although patients with ATTRwt exhibited higher median N-terminal pro-brain natriuretic peptide (6467 vs. 3173 pg/L; P = 0.019), median troponin I (0.135 vs. 0.025 µg/L; P < 0.001), mean LV maximal wall thickness (17 ± 3.4 vs. 14 ± 2.5 mm; P = 0.001), rate of pericardial effusion (44 vs. 19%; P = 0.047), and rate of pacemakers (44 vs. 12%; P = 0.004), clinical overlap between ATTRwt and other HFpEF forms was high. CONCLUSION: ATTRwt is an underdiagnosed disease that accounts for a significant number (13%) of HFpEF cases. The effect of emerging TTR-modifying drugs should be evaluated in these patients.

Spreading of pollutants from alkaline mine drainage. Rodalquilar mining district (SE Spain).

In the Rodalquilar mining district of SE Spain, a total of 46 soil samples that were between 0 and 20 cm in depth were taken from the tailings dump, stream sediments, and surfaces that were presumably were unaffected by mining. In each soil sample, organic carbon content, pH, particle size distribution and total and soluble trace element content were analysed. Pollutants were scattered by runoff from two source areas: tailings from Au mining (Sn, Sb, As and Se) and wastes from Pb mining (Pb, Cu and Zn). Sn, Pb, and Sb were spread mostly in the solid phase of the runoff, while Cu, Zn, As and Se were spread in both the solid and soluble phases of the runoff. The pollutants with the highest soluble concentrations were As and Se, which were scattered at greater distances from the source. Some evidence suggests that tailings from Au mining could also be scattered by wind, but no farther than 1500 m from the source.

Impact of unconfined sulphur-mine waste on a semi-arid environment (Almería, SE Spain).

Thirty-five soil samples were taken from unconfined mine waste, stream sediments, and surfaces unoccupied by mining and presumably unaffected by it, in a sulphur-mining zone surrounded by carbonate material and characterized by a semi-arid climate with short torrential storms. These samples were analysed and the results compared to estimate the spread of pollution in the landscape and to assess potential environmental risk. The mean concentrations of S, Zn, Cd, Pb, and As in mine waste were between 3.5-fold (As) and 50-fold (S) greater than unaffected soils. Oxidation of S led to a sharp drop in pH, strong weathering of minerals, and solubilisation of the constituent elements, forming a toxic acidic mine drainage with highly concentrated pollutants that were discharged into the drainage channels. Successive acid mine drainage into the soil on the valley floor spreads acidification and pollution downstream. The high carbonate content in surrounding soils played an important role in the increase of the pH and precipitation of S, Pb, and Al of the affected soils. Meanwhile, high mobility of Zn, Cd and As under basic conditions and a low Fe concentration explain the broad spread of these elements, as high concentrations were detected in soil more than 2000 m from the source. Only the soil solutions from near the waste dump (first 500 m) were highly phytotoxic, and moderately phytotoxic from 500 to 1500 m away. The concentration of pollutants in the leachates was clearly higher than in soil solutions, even in the soils located over 2000 m from the source, implying that the size of the polluted area will increase with time.

Clinical profile and outcome of cardiac amyloidosis in a Spanish referral center.

INTRODUCTION AND OBJECTIVES: Cardiac amyloidosis (CA) is produced by amyloid fiber deposition in the myocardium. The most frequent forms are those caused by light chains (AL) and transthyretin (ATTR). Our objective was to describe the diagnosis, treatment and outcomes of CA in a specialized Spanish center. METHODS: We included all patients diagnosed with CA in Hospital Universitario Puerta de Hierro Majadahonda from May 2008 to September 2018. We analyzed their clinical characteristics, outcomes, and survival. RESULTS: We included 180 patients with CA, of whom 64 (36%) had AL (50% men; mean age, 65±11 years) and 116 had ATTR (72% men; mean age 79±11 years; 18 with hereditary ATTR). The most common presentation was heart failure in both groups (81% in AL and 45% in ATTR, P <.01). Other forms of presentation in ATTR patients were atrial arrhythmias (16%), conduction disorders (6%), and incidental finding (6%); 70 patients (40%), had a previous alternative cardiac diagnosis. Diagnosis was noninvasive in 75% of ATTR patients. Diagnostic delay was higher in ATTR (2.8±4.3 vs 0.6±0.7 years, P <.001), but mortality was greater in AL patients (48% vs 32%, P=.028). Independent predictors of mortality were AL subtype (HR, 6.16; 95%CI, 1.56-24.30; P=.01), female sex (HR, 2.35; 95%CI, 1.24-4.46; P=.01), and NYHA functional class III-IV (HR, 2.07; 95%CI, 1.11-3.89; P=.02). CONCLUSIONS: CA is a clinical challenge, with wide variability in its presentation depending on the subtype, leading to diagnostic delay and high mortality. Improvements are needed in the early diagnosis and treatment of these patients.

Cardiac scintigraphy with 99mTc-diphosphonates in cardiac amyloidosis. / Gammagrafía cardíaca con 99mTc-difosfonatos en la amiloidosis cardíaca.

Transthyretin cardiac amyloidosis (ATTR) has traditionally been considered a rare, difficult-to-diagnose and untreatable disease. However, its prevalence is known to be greater than what was previously thought, non-invasive diagnostic methods are available, and that effective treatments are emerging. In this context, cardiac scintigraphy (CS) with 99mTc-labelled diphosphonates has aroused a noticeable surge in interest by demonstrating high sensitivity and specificity for the reliable, non-invasive diagnosis of ATTR. By way of a guide, this article aims to identify the critical components in the performance of CS that are useful in everyday clinical practice and, thus, help specialists use optimal radiopharmaceuticals, obtain the most appropriate images, interpret the results thereof, and acquaint themselves with those clinical scenarios in which it is convenient to perform CS.

From the limits of the classical model of sensitometric curves to a realistic model based on the percolation theory for GafChromic EBT films.

PURPOSE: Modern radiotherapy uses complex treatments that necessitate more complex quality assurance procedures. As a continuous medium, GafChromic EBT films offer suitable features for such verification. However, its sensitometric curve is not fully understood in terms of classical theoretical models. In fact, measured optical densities and those predicted by the classical models differ significantly. This difference increases systematically with wider dose ranges. Thus, achieving the accuracy required for intensity-modulated radiotherapy (IMRT) by classical methods is not possible, plecluding their use. As a result, experimental parametrizations, such as polynomial fits, are replacing phenomenological expressions in modern investigations. This article focuses on identifying new theoretical ways to describe sensitometric curves and on evaluating the quality of fit for experimental data based on four proposed models. METHODS: A whole mathematical formalism starting with a geometrical version of the classical theory is used to develop new expressions for the sensitometric curves. General results from the percolation theory are also used. A flat-bed-scanner-based method was chosen for the film analysis. Different tests were performed, such as consistency of the numeric results for the proposed model and double examination using data from independent researchers. RESULTS: Results show that the percolation-theory-based model provides the best theoretical explanation for the sensitometric behavior of GafChromic films. The different sizes of active centers or monomer crystals of the film are the basis of this model, allowing acquisition of information about the internal structure of the films. Values for the mean size of the active centers were obtained in accordance with technical specifications. In this model, the dynamics of the interaction between the active centers of GafChromic film and radiation is also characterized by means of its interaction cross-section value. CONCLUSIONS: The percolation model fulfills the accuracy requirements for quality-control procedures when large ranges of doses are used and offers a physical explanation for the film response.

Prevalence of Cardiac Amyloidosis in Patients with Carpal Tunnel Syndrome.

Carpal tunnel syndrome (CTS) is a common finding among patients with cardiac amyloidosis. We sought to determine the prevalence of cardiac amyloidosis in patients who had undergone CTS surgery. From 2005 to 2014, 308 patients ≥ 60 years underwent CTS surgery. Of these, 233 (76%) agreed to participate in the study and 101 (73 ± 8 years; 68% females) showed left ventricular hypertrophy (LVH) ≥ 12 mm and underwent additional studies to diagnose AL and ATTR amyloidosis. Based on complementary studies, three patients were diagnosed with cardiac amyloidosis (two wild-type ATTR and one AL). The three patients showed bilateral CTS with no occupational risk factors. Prevalence of cardiac amyloidosis in the overall cohort was only 1.2% (3/233), but among patients with LVH and bilateral CTS, the prevalence was 5.5% (3/55) and 13.6% (3/22) if cases with an occupational risk factor were excluded. Cardiac amyloidosis should be excluded in the presence of bilateral CTS and particularly if an occupational risk factor is absent.

Prevalence of cardiac amyloidosis among elderly patients with systolic heart failure or conduction disorders.

Objective: Cardiac amyloid infiltration can lead to systolic heart failure (HF) or to conduction disorders (CD). Patients with transthyretin (ATTR) amyloidosis are particularly exposed. We sought to determine the prevalence of ATTR and AL among patients >60 years admitted with CD or unexplained systolic HF and increased wall thickness. Materials and Methods: We studied 143 patients (57% males, 79 ± 9 years) with HF (N = 28) or CD requiring pacemaker implantation (N = 115). In total, 139 (97%) patients (28 with HF and 111 with CD) underwent 99mTc-DPD scintigraphy to detect ATTR, and 105 (73%; 19 HF and 86 CD) underwent AL screening. Results: Five patients (4%; 95%CI:0-7%) exhibited wild-type ATTR (ATTRwt) amyloidosis, 2 (2%; 95%CI:0-4%) had CD and 3 (11%; 95%CI:0-23%) HF. No patient showed AL. The 2 ATTRwt patients with CD were previously asymptomatic, did not show classical ECG signs and exhibited mild LV hypertrophy with preserved LVEF. By contrast, all ATTRwt patients with HF had ECG and echocardiographic signs of amyloid. During a mean follow-up of 18 ± 11 months, 3(60%) patients with ATTRwt amyloidosis (1 CD and 2 HF) and 14(10.4%) without died. Conclusion: Prevalence of ATTRwt amyloidosis in patients with CD requiring pacemaker is low. Although, additional studies are needed, prevalence seems to be higher in elderly patients with systolic HF.

Remediation measures and displacement of pollutants in soils affected by the spill of a pyrite mine.

The soils affected by the spill of a pyrite mine were analysed in 100 sampling points at three depths (0-10, 10-30, and 30-50 cm) in 1998 (after the tailings were removed), 1999 (after the cleaning of the highly contaminated areas), and 2004 (after the tilling of the upper 20-25 cm). The comparative study reveals that the removal of the tailings left a heterogeneous distribution pattern of the contaminants, with highly polluted spots alternating with less contaminated areas. The cleanup did not substantially lower the concentration in the highly polluted soils, and the spread of the pollutants increased the concentration in As and Pb in the uppermost 10 cm of 60% of the soils, while the Zn and Cd concentrations increased in only 30% of the soils. Given the high concentration of pollutants in the topsoil (especially As), the tilling of the upper 20-25 cm, despite reducing the average concentration of pollutants in the uppermost 10 cm, did not substantially lower the percentage of soils that exceeded the concentration of 40 mg As kg(-1) dry soil and almost doubled the percentage of soils that surpassed this concentration between 10 and 30 cm. Meanwhile, the displacement of Zn and Cd within the soil supported the reduction in the percentage of soils that in the upper 10 cm exceeded the reference concentrations of these elements (900 mg Zn kg(-1) dry soil and 2 mg Cd kg(-1) dry soil), and the percentage of soils exceeding these concentrations between 10 and 50 cm in depth did not increase. Six years after the spill and at the end of all remediation measures, the intervention levels defined by the Environmental Agency of the Regional Government of Andalusia for natural parks were exceeded in the uppermost 10 cm in 35% of the soils.

[Non traumatic posterior instability in primary total knee replacement and its revision]. / Inestabilidad posterior no traumática de prótesis de rodilla primaria y su revisión.

BACKGROUND: Dislocation after total knee arthroplasty is a rare complication and a difficult problem to address. When the flexion gap is larger than the extension gap and the collateral ligaments are injured, instability and knee arthroplasty dislocation can occur. MATERIAL AND METHODS: We report the case of a patient presenting with a posterior dislocation of a posterior-stabilized prosthesis without trauma. Frank instability in varus stress test and a positive anterior drawer test with tibial internal rotation dismissed the conservative treatment. RESULTS: A constrained condylar prosthesis was used for the revision. He suffered a similar episode after a month, which demonstrated that the increase in the level of constraint was not enough to correct the severe asymmetric instability in flexion due to the damaged external structures. A rotating-hinge prosthesis was then implanted and the patient reported no additional episodes of instability. CONCLUSIONS: We made an exhaustive review of the literature, analyzed the possible causes that can lead to the tibiofemoral instability after a total knee arthroplasty and described some technical considerations.

La luxación tras la artroplastía de rodilla es una complicación poco frecuente y de difícil manejo. Una brecha en flexión demasiado grande asociada a una laxitud de los ligamentos colaterales puede llevar a la inestabilidad y a la luxación en flexión.

[Quality of life of patients with asthma on beclomethasone/formoterol. Cost-utility analysis]. / Calidad de vida del paciente asmático con beclometasona/formoterol. Análisis de coste-utilidad.

AIM: To perform a cost-utility analysis on asthmatic patients on beclomethasone/formoterol fixed combination in Primary Health Care. Material and methods Non-probability sampling was used to select a group of asthmatic patients with moderate/severe persistent severity (GEMA 2009), treated with beclomethasone/formoterol fixed combination, over 18 years, had given their informed consent. The study observation period was 6 months. The variables studied were: age, sex, duration of disease, health resources used, analysis of health related quality of life by EQ-5D and SF-36, and the specific Asthma Quality of Life Questionnaire. For the qualitative variables, the frequency and percentages were calculated, and for the quantitative variables, the mean, SD and 95% CI. Chi-square, Student t-test and ANOVA were used for statistical inference. Comparisons were made with a statistical significance of 0.05. RESULTS: Of the 64 patients that completed the study, 59.4% were female. The mean age was 49 years, and mean disease duration was 93 months. For asthma control, 53% of patients had a prescription pattern of one/12h. All health related quality of life scales were modified with respect to the baseline and the differences were statistically significant. Our patients had a better health related quality of life than Spanish asthma cohort. The incremental cost utility beclomethasone/formoterol versus usual treatment option was € 6,256/QALY.

[Primary carcinoma of the trachea (author's transl)]. / Carcinoma primitivo de tráquea.

Dyspnea was the only significant clinical symptom in a patient suffering from a primary tracheal tumor. Tracheography and tracheal tomography revealed a marked stenosis in the medium third of this organ. The endoscopic biopsy identified a squamous carcinoma. Medical treatment and radiation gave only temporary tumor control. The uncommoness of primary tracheal neoplasms, one per each 180 cases of lung tumor, is stressed. The diagnosis is usually made in advanced stages due to the lack of initial symptoms and because these patients are frequently catalogued as asthmatics or bronchitics. Performance of flow-volume loops using a mixture of helium and oxygen increases the diagnostic percentages, since it is possible to separate those cases with diffuse airway obstruction.

Inervación simpática cardiaca y terapias apropiadas en pacientes portadores de desfibrilador automático implantado en prevención primaria / Cardiac sympathetic innervation and appropriate therapies in patients with an implantable cardioverter-defibrillator in primary prevention

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Effectiveness of amendments on the spread and phytotoxicity of contaminants in metal-arsenic polluted soil.

A metal-arsenic polluted soil from sulphide-mine waste was treated, in all possible combinations, with two different amounts of marble sludge (98% CaCO3), compost (41% organic carbon), and Byferrox (70% Fe). Lixiviate and pore water from each treated and untreated soil were analysed, and lettuce-seed bioassays were performed. None of the treatments decreased the electrical conductivity of lixiviates or the concentrations of all pollutants found in both solutions. Marble sludge and compost increased the pH values and decreased the zinc, cadmium, copper, and lead concentrations in both solutions while increasing the arsenic concentrations in the lixiviates. Byferrox did not alter the physicochemical parameters or the concentrations of zinc, cadmium, copper, or lead in either solution but significantly decreased the arsenic concentrations in pore water. Compared with the Byferrox treatment, the mixture of marble sludge and Byferrox decreased redox potential values, increasing the arsenic concentrations in both solutions and the electrical conductivity of the pore water. All lixiviates were highly phytotoxic and seeds did not germinate. Pore-water phytotoxicity was related to electrical conductivity values and heavy-metal concentrations. The combination of marble sludge and compost was most effective at diminishing toxicity in lettuce. The soils treated with Byferrox, alone or mixed with marble sludge or compost, were the most phytotoxic.

Role of cardiac scintigraphy with 99mTc-DPD in the differentiation of cardiac amyloidosis subtype.

INTRODUCTION AND OBJECTIVES: We investigated the diagnostic accuracy of (99m)Tc-3,3-diphosphono-1,2 propanodicarboxylic acid ((99m)Tc-DPD) scintigraphy in differentiating between monoclonal immunoglobulin light chain and transthyretin-related cardiac amyloidosis. METHODS: Nineteen patients with documented cardiac amyloidosis were included: 8 with transthyretin-related amyloidosis (group A) and 11 with light chain amyloidosis (group B). All the patients underwent scintigraphy with (99m)Tc-DPD and (99m)Tc-methylene diphosphonate ((99m)Tc-MDP). RESULTS: On visual scoring, cardiac (99m)Tc-DPD uptake could be characterized as moderate to severe (scores of 2-3), with ventricular or biventricular distribution, in all group A patients (transthyretin-related cardiac amyloidosis), and was absent or mild (scores of 0-1) and diffusely distributed in all group B patients (monoclonal immunoglobulin light chain cardiac amyloidosis). (99m)Tc-DPD uptake was also absent (score of 0) among unaffected controls and in 2 unaffected relatives of patients with hereditary transthyretin-related amyloidosis who harbor a mutation in the TTR gene. With (99m)Tc-MDP, all the patients had a myocardial uptake score of 0-1. In our series, selective myocardial uptake of (99m)Tc-DPD provided 100% accuracy (95% confidence interval, 97.37%-100%) for the differentiation between transthyretin-related and monoclonal immunoglobulin light chain cardiac amyloidosis. CONCLUSIONS: We conclude that (99m)Tc-DPD scintigraphy is a useful test for the differential diagnosis of transthyretin vs monoclonal immunoglobulin light chain etiology in patients with cardiac amyloidosis.