Reply to the editor

We appreciate the comments and concerns expressed by Arakawa and colleagues regarding our article, titled “Pulsatile control of rotary blood pumps: Does the modulation waveform matter?”1 Unfortunately, we have to disagree with Arakawa and colleagues. As is obvious from the title of our article, it investigates the effect of different waveforms on the heart–device interaction. In contrast to the authors' claim, this is the first article in the literature that uses basic waveforms (sine, triangle, saw tooth, and rectangular) with different phase shifts to examines their impact on left ventricular unloading. The previous publications2, 3 and 4 just varied the pump speed during systole and diastole, which was first reported by Bearnson and associates5 in 1996, and studied its effect on aortic pressure, coronary flow, and end-diastolic volume. We should mention that dp/dtmax is a load-sensitive parameter of contractility and not representative for the degree of unloading. Moreover, none of the aforementioned reports has studied mechanical unloading and in particular the stroke work of the left ventricle. Our method is unique because we do not just alternate between high and low speed but have accurate control of the waveform because of the direct drive system of Levitronix Technologies LLC (Waltham, Mass) and a custom-developed pump controller. Without referring, Arakawa and associates state “several previous studies have already reported the coronary flow diminishes as the left ventricular assist device support increases.” It should be noted that all the waveforms used in our study have 2000 rpm average value with 1000 rpm amplitude, which is not an excessive speed for the CentriMag rotary pump (Levitronix) to collapse the ventricle and diminish the coronary flow. We agree with Arakawa and coworkers that there is a need for a heart failure model to come to more relevant results with respect to clinical expectations. However, we have explored many existing models, including species and breeds that have a native proneness to cardiomyopathy, but all of them differ from the genetic presentation in humans. We certainly do not believe that the use of microembolization, in which the coronary circulation is impaired by the injection of microspheres, would form a good model from which to draw conclusions about coronary flow change under different loading conditions. A model would be needed in which either an infarct is created to mimic ischemic heart failure or the coronary circulation remains untouched to simulate, for instance, dilated cardiomyopathy. Furthermore, in discussion we clearly mention that “lack of heart failure is a major limitation of our study.” We also believe that unloading is not the only factor of the cardiac functional recovery, and an excessive unloading of the left ventricle might lead to cardiac tissue atrophy. Therefore, in our article we mention that control of the level of cardiac unloading by assist devices has been suggested as a mechanical tool to promote recovery, and more studies are required to find better strategies for the speed modulation of rotary pumps and to achieve an optimal heart load control to enhance myocardial recovery. Finally, there are many publications about pulsing rotary blood pumps and it was impossible to include them all. We preferred to reference some of the earlier basic works such as an original research by Bearnson and coworkers5 and another article published by our group,6 which is more relevant.

Cardiolipin biosynthesis and remodeling enzymes are altered during development of heart failure.

Cardiolipin (CL) is responsible for modulation of activities of various enzymes involved in oxidative phosphorylation. Although energy production decreases in heart failure (HF), regulation of cardiolipin during HF development is unknown. Enzymes involved in cardiac cardiolipin synthesis and remodeling were studied in spontaneously hypertensive HF (SHHF) rats, explanted hearts from human HF patients, and nonfailing Sprague Dawley (SD) rats. The biosynthetic enzymes cytidinediphosphatediacylglycerol synthetase (CDS), phosphatidylglycerolphosphate synthase (PGPS) and cardiolipin synthase (CLS) were investigated. Mitochondrial CDS activity and CDS-1 mRNA increased in HF whereas CDS-2 mRNA in SHHF and humans, not in SD rats, decreased. PGPS activity, but not mRNA, increased in SHHF. CLS activity and mRNA decreased in SHHF, but mRNA was not significantly altered in humans. Cardiolipin remodeling enzymes, monolysocardiolipin acyltransferase (MLCL AT) and tafazzin, showed variable changes during HF. MLCL AT activity increased in SHHF. Tafazzin mRNA decreased in SHHF and human HF, but not in SD rats. The gene expression of acyl-CoA: lysocardiolipin acyltransferase-1, an endoplasmic reticulum MLCL AT, remained unaltered in SHHF rats. The results provide mechanisms whereby both cardiolipin biosynthesis and remodeling are altered during HF. Increases in CDS-1, PGPS, and MLCL AT suggest compensatory mechanisms during the development of HF. Human and SD data imply that similar trends may occur in human HF, but not during nonpathological aging, consistent with previous cardiolipin studies.

Increased myocardial susceptibility to repetitive ischemia with high-fat diet-induced obesity.

Obesity and diabetes are frequently associated with cardiovascular disease. When a normal heart is subjected to brief/sublethal repetitive ischemia and reperfusion (I/R), adaptive responses are activated to preserve cardiac structure and function. These responses include but are not limited to alterations in cardiac metabolism, reduced calcium responsiveness, and induction of antioxidant enzymes. In a model of ischemic cardiomyopathy inducible by brief repetitive I/R, we hypothesized that dysregulation of these adaptive responses in diet-induced obese (DIO) mice would contribute to enhanced myocardial injury. DIO C57BL/6J mice were subjected to 15 min of daily repetitive I/R while under short-acting anesthesia, a protocol that results in the development of fibrotic cardiomyopathy. Cardiac lipids and candidate gene expression were analyzed at 3 days, and histology at 5 days of repetitive I/R. Total free fatty acids (FFAs) in the cardiac extracts of DIO mice were significantly elevated, reflecting primarily the dietary fatty acid (FA) composition. Compared with lean controls, cardiac FA oxidation (FAO) capacity of DIO mice was significantly higher, concurrent with increased expression of FA metabolism gene transcripts. Following 15 min of daily repetitive I/R for 3 or 5 days, DIO mice exhibited increased susceptibility to I/R and, in contrast to lean mice, developed microinfarction, which was associated with an exaggerated inflammatory response. Repetitive I/R in DIO mice was associated with more profound significant downregulation of FA metabolism gene transcripts and elevated FFAs and triglycerides. Maladaptive metabolic changes of FA metabolism contribute to enhanced myocardial injury in diet-induced obesity.

Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis

Septic shock is characterized by increased vascular permeability and hypotension despite increased cardiac output. Numerous vasoactive cytokines are upregulated during sepsis, including angiopoietin 2 (ANG2), which increases vascular permeability. Here we report that mice engineered to inducibly overexpress ANG2 in the endothelium developed sepsis-like hemodynamic alterations, including systemic hypotension, increased cardiac output, and dilatory cardiomyopathy. Conversely, mice with cardiomyocyte-restricted ANG2 overexpression failed to develop hemodynamic alterations. Interestingly, the hemodynamic alterations associated with endothelial-specific overexpression of ANG2 and the loss of capillary-associated pericytes were reversed by intravenous injections of adeno-associated viruses (AAVs) transducing cDNA for angiopoietin 1, a TIE2 ligand that antagonizes ANG2, or AAVs encoding PDGFB, a chemoattractant for pericytes. To confirm the role of ANG2 in sepsis, we i.p. injected LPS into C57BL/6J mice, which rapidly developed hypotension, acute pericyte loss, and increased vascular permeability. Importantly, ANG2 antibody treatment attenuated LPS-induced hemodynamic alterations and reduced the mortality rate at 36 hours from 95% to 61%. These data indicate that ANG2-mediated microvascular disintegration contributes to septic shock and that inhibition of the ANG2/TIE2 interaction during sepsis is a potential therapeutic target.

Swiss national guideline for reimbursement of enzyme replacement therapy in late-onset Pompe disease.

Glycogen storage disease type II is a rare multi-systemic disorder characterised by an intracellular accumulation of glycogen due a mutation in the acid alpha glucosidase (GAA) gene. The level of residual enzyme activity, the genotype and other yet unknown factors account for the broad variation of the clinical phenotype. The classical infantile form is characterised by severe muscle hypotonia and cardiomyopathy leading to early death. The late-onset form presents as a limb girdle myopathy with or without pulmonary dysfunction. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) in infants is life saving. In contrast, therapeutic efficacy of rhGAA in the late-onset form is modest. High expenses of rhGAA, on-going infusions and poor pharmacokinetic efficacy raised a discussion of the cost effectiveness of ERT in late-onset Pompe disease in Switzerland. This discussion was triggered by a Swiss federal court ruling which confirmed the reluctance of a health care insurer not to reimburse treatment costs in a 67-year-old female suffering from Pompe disease. As a consequence of this judgement ERT was stopped by all insurance companies in late-onset Pompe patients in Switzerland regardless of their clinical condition. Subsequent negotiations lead to the release of a national guideline of the management of late-onset Pompe disease. Initiation and limitation of ERT is outlined in a national Pompe registry. Reimbursement criteria are defined and individual efficacy of ERT with rhGAA is continuously monitored.

Lack of efficacy of low-dose spironolactone as adjunct treatment to conventional congestive heart failure treatment in dogs.

Aldosterone plays an important role in the pathophysiology of heart failure. Aldosterone receptor blockade has been shown to reduce morbidity and mortality in human patients with advanced congestive left ventricular heart failure. This study was designed to assess the efficacy and tolerance of long-term low-dose spironolactone when added to conventional heart failure treatment in dogs with advanced heart failure. Eighteen client-owned dogs with advanced congestive heart failure due to either degenerative valve disease (n=11) or dilated cardiomyopathy (n=7) were included in this prospective, placebo-controlled, double-blinded, randomized clinical study. After initial stabilization including furosemide, angiotensin-converting enzyme inhibitors, pimobendan and digoxin, spironolactone at a median dose of 0.52 mg/kg (range 0.49-0.8 mg/kg) once daily (n=9) or placebo (n=9) was added to the treatment, and the dogs were reassessed 3 and 6 months later. Clinical scoring, echocardiography, electrocardiogram, systolic blood pressure measurement, thoracic radiography, sodium, potassium, urea, creatinine, alanine aminotransferase, aldosterone and aminoterminal atrial natriuretic propeptide were assessed at baseline, 3 and 6 months. Survival times were not significantly different between the two treatment groups. Spironolactone was well tolerated when combined with conventional heart failure treatment.

Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers

Antisense oligonucleotides (AONs) hold promise for therapeutic correction of many genetic diseases via exon skipping, and the first AON-based drugs have entered clinical trials for neuromuscular disorders1, 2. However, despite advances in AON chemistry and design, systemic use of AONs is limited because of poor tissue uptake, and recent clinical reports confirm that sufficient therapeutic efficacy has not yet been achieved. Here we present a new class of AONs made of tricyclo-DNA (tcDNA), which displays unique pharmacological properties and unprecedented uptake by many tissues after systemic administration. We demonstrate these properties in two mouse models of Duchenne muscular dystrophy (DMD), a neurogenetic disease typically caused by frame-shifting deletions or nonsense mutations in the gene encoding dystrophin3, 4 and characterized by progressive muscle weakness, cardiomyopathy, respiratory failure5 and neurocognitive impairment6. Although current naked AONs do not enter the heart or cross the blood-brain barrier to any substantial extent, we show that systemic delivery of tcDNA-AONs promotes a high degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a lesser extent, the brain. Our results demonstrate for the first time a physiological improvement of cardio-respiratory functions and a correction of behavioral features in DMD model mice. This makes tcDNA-AON chemistry particularly attractive as a potential future therapy for patients with DMD and other neuromuscular disorders or with other diseases that are eligible for exon-skipping approaches requiring whole-body treatment.

Cardiac medication during pregnancy, data from the ROPAC

BACKGROUND Data on pharmacological management during pregnancy are scarce. The aim of this study was to describe the type and frequency of cardiac medication used in pregnancy in patients with cardiovascular disease and to assess the relationship between medication use and fetal outcome. METHODS AND RESULTS Between 2007 and 2011 sixty hospitals in 28 countries enrolled 1321 pregnant women. All patients had structural heart disease (congenital 66%, valvular 25% or cardiomyopathy 7% or ischemic 2%). Medication was used by 424 patients (32%) at some time during pregnancy: 22% used beta-blockers, 8% antiplatelet agents, 7% diuretics, 2.8% ACE inhibitors and 0.5% statins. Compared to those who did not take medication, patients taking medication were older, more likely to be parous, have valvular heart disease and were less often in sinus rhythm. The odds ratio of fetal adverse events in users versus non-users of medication was 2.6 (95% CI 2.0-3.4) and after adjustment for cardiac and obstetric parameter was 2.0 (95% CI 1.4-2.7). Babies of patients treated with beta-blockers had a significantly lower adjusted birth weight (3140 versus 3240 g, p = 0.002). The highest rate of fetal malformation was found in patients taking ACE inhibitors (8%). CONCLUSION One third of pregnant women with heart disease used cardiac medication during their pregnancy, which was associated with an increased rate of adverse fetal events. Birth weight was significantly lower in children of patients taking beta-blockers. A randomized trial is needed to distinguish the effects of the medication from the effects of the underlying maternal cardiac condition.

Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement.

OBJECTIVE Short-chain enoyl-CoA hydratase (ECHS1) is a multifunctional mitochondrial matrix enzyme that is involved in the oxidation of fatty acids and essential amino acids such as valine. Here, we describe the broad phenotypic spectrum and pathobiochemistry of individuals with autosomal-recessive ECHS1 deficiency. METHODS Using exome sequencing, we identified ten unrelated individuals carrying compound heterozygous or homozygous mutations in ECHS1. Functional investigations in patient-derived fibroblast cell lines included immunoblotting, enzyme activity measurement, and a palmitate loading assay. RESULTS Patients showed a heterogeneous phenotype with disease onset in the first year of life and course ranging from neonatal death to survival into adulthood. The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10). Serum lactate was elevated and brain magnetic resonance imaging showed white matter changes or a Leigh-like pattern resembling disorders of mitochondrial energy metabolism. Analysis of patients' fibroblast cell lines (6/10) provided further evidence for the pathogenicity of the respective mutations by showing reduced ECHS1 protein levels and reduced 2-enoyl-CoA hydratase activity. While serum acylcarnitine profiles were largely normal, in vitro palmitate loading of patient fibroblasts revealed increased butyrylcarnitine, unmasking the functional defect in mitochondrial β-oxidation of short-chain fatty acids. Urinary excretion of 2-methyl-2,3-dihydroxybutyrate - a potential derivative of acryloyl-CoA in the valine catabolic pathway - was significantly increased, indicating impaired valine oxidation. INTERPRETATION In conclusion, we define the phenotypic spectrum of a new syndrome caused by ECHS1 deficiency. We speculate that both the β-oxidation defect and the block in l-valine metabolism, with accumulation of toxic methacrylyl-CoA and acryloyl-CoA, contribute to the disorder that may be amenable to metabolic treatment approaches.

Analytical, physiologic, and clinical validation of a radioimmunoassay for measurement of procollagen type III amino terminal propeptide in serum and bronchoalveolar lavage fluid obtained from dogs.

OBJECTIVE To validate a radioimmunoassay for measurement of procollagen type III amino terminal propeptide (PIIINP) concentrations in canine serum and bronchoalveolar lavage fluid (BALF) and investigate the effects of physiologic and pathologic conditions on PIIINP concentrations. SAMPLE POPULATION Sera from healthy adult (n = 70) and growing dogs (20) and dogs with chronic renal failure (CRF; 10), cardiomyopathy (CMP; 12), or degenerative valve disease (DVD; 26); and sera and BALF from dogs with chronic bronchopneumopathy (CBP; 15) and healthy control dogs (10 growing and 9 adult dogs). PROCEDURE A radioimmunoassay was validated, and a reference range for serum PIIINP (S-PIIINP) concentration was established. Effects of growth, age, sex, weight, CRF, and heart failure on S-PIIINP concentration were analyzed. In CBP-affected dogs, S-PIIINP and BALF-PIIINP concentrations were evaluated. RESULTS The radioimmunoassay had good sensitivity, linearity, precision, and reproducibility and reasonable accuracy for measurement of S-PIIINP and BALF-PIIINP concentrations. The S-PIIINP concentration reference range in adult dogs was 8.86 to 11.48 mug/L. Serum PIIINP concentration correlated with weight and age. Growing dogs had significantly higher S-PIIINP concentrations than adults, but concentrations in CRF-, CMP-, DVD-, or CBP-affected dogs were not significantly different from control values. Mean BALF-PIIINP concentration was significantly higher in CBP-affected dogs than in healthy adults. CONCLUSIONS AND CLINICAL RELEVANCE In dogs, renal or cardiac disease or CBP did not significantly affect S-PIIINP concentration; dogs with CBP had high BALF-PIIINP concentrations. Data suggest that the use of PIIINP as a marker of pathologic fibrosis might be limited in growing dogs.

Rescue of neonatal cardiac dysfunction in mice by administration of cardiac progenitor cells in utero

Striated preferentially expressed gene (Speg) is a member of the myosin light chain kinase family. We previously showed that disruption of the Speg gene locus in mice leads to a dilated cardiomyopathy with immature-appearing cardiomyocytes. Here we show that cardiomyopathy of Speg(-/-) mice arises as a consequence of defects in cardiac progenitor cell (CPC) function, and that neonatal cardiac dysfunction can be rescued by in utero injections of wild-type CPCs into Speg(-/-) foetal hearts. CPCs harvested from Speg(-/-) mice display defects in clone formation, growth and differentiation into cardiomyocytes in vitro, which are associated with cardiac dysfunction in vivo. In utero administration of wild-type CPCs into the hearts of Speg(-/-) mice results in CPC engraftment, differentiation and myocardial maturation, which rescues Speg(-/-) mice from neonatal heart failure and increases the number of live births by fivefold. We propose that in utero administration of CPCs may have future implications for treatment of neonatal heart diseases.

Cellular hyper-excitability caused by mutations that alter the activation process of voltage-gated sodium channels.

Voltage-gated sodium channels (Nav) are widely expressed as macro-molecular complexes in both excitable and non-excitable tissues. In excitable tissues, the upstroke of the action potential is the result of the passage of a large and rapid influx of sodium ions through these channels. NaV dysfunction has been associated with an increasingly wide range of neurological, muscular and cardiac disorders. The purpose of this review is to summarize the recently identified sodium channel mutations that are linked to hyper-excitability phenotypes and associated with the alteration of the activation process of voltage gated sodium channels. Indeed, several clinical manifestations that demonstrate an alteration of tissue excitability were recently shown to be strongly associated with the presence of mutations that affect the activation process of the Nav. These emerging genotype-phenotype correlations have expanded the clinical spectrum of sodium channelopathies to include disorders which feature a hyper-excitability phenotype that may or may not be associated with a cardiomyopathy. The p.I141V mutation in SCN4A and SCN5A, as well as its homologous p.I136V mutation in SCN9A, are interesting examples of mutations that have been linked to inherited hyperexcitability myotonia, exercise-induced polymorphic ventricular arrhythmias and erythromelalgia, respectively. Regardless of which sodium channel isoform is investigated, the substitution of the isoleucine to valine in the locus 141 induces similar modifications in the biophysical properties of the Nav by shifting the voltage-dependence of steady state activation toward more negative potentials.

Persistently elevated troponin I in heart failure patients - a suitable prognosticator and a possible boon to public health?

Baseline elevation of troponin I (TnI) has been associated with worse outcomes in heart failure (HF). However, the prevalence of persistent TnI elevation and its association with clinical outcomes has not been well described. HF is a major public health issue due to its wide prevalence and prognosticators of this condition will have a significant impact on public health. Methods: A retrospective study was performed in 510 patients with an initial HF admission between 2002 to 2004, and all subsequent hospital admissions up to May 2009 were recorded in a de-identified database. Persistent TnI elevation was defined as a level ≥0.05 ng/ml on ≥3 HF admissions. Baseline characteristics, hospital readmissions and all cause mortality were compared between patients with persistent TnI elevation (Persistent), patients with no persistence of TnI (Nonpersistent) and patients who had less than three hospital admissions (admission <3) groups. Also the same data was analyzed using the mean method in which the mean value of all recorded troponin values of each patient was used to define persistence i.e. patients who had a mean troponin level ≥0.05 ng/ml were classified as persistent. Results: Mean age of our cohort was 68.4 years out of which 99.6% subjects were male, 62.4% had ischemic HF. 78.2% had NYHA class III to IV HF, mean LVEF was 25.9%. Persistent elevation of TnI was seen in 26% of the cohort and in 66% of patients with more than 3 hospital admissions. Mean TnI level was 0.67 ± 0.15 ng/ml in the 'Persistent' group. Mean TnI using the mean method was 1.11 ± 7.25 ng/ml. LVEF was significantly lower in persistent group. Hypertension, diabetes, chronic renal insufficiency and mean age did not differ between the two groups. 'Persistent' patients had higher mortality (HR = 1.26, 95% CI = 0.89–1.78, p = 0.199 when unadjusted and HR = 1.29, 95% CI = 0.89–1.86, p = 0.176 when adjusted for race, LVEF and ischemic etiology) HR for mortality in persistent patients was 1.99 (95% CI = 1.06–3.73, p = 0.03) using the mean method. The following results were found in those with ischemic cardiomyopathy (HR = 1.44034, 95% CI = 0.92–2.26, p = 0.113) and (HR = 1.89, 95% CI = 1.01–3.55, p = 0.046) by using the mean method. 2 out of three patients with HF who were readmitted three or more times had persistent elevation of troponin I levels. Patients with chronic persistence of troponin I elevation showed a trend towards lesser survival as compared to patients who did not have chronic persistence, however this did not reach statistical significance. This trend was seen more among ischemic patients than non ischemic patients, but did not reach statistical significance. With the mean method, patients with chronic persistence of troponin I elevation had significantly lesser survival than those without it. Also ischemic patients had significantly lesser survival than non ischemic patients. ^

3D Wavelet-based Fusion Techniques for Biomedical Imaging

Hoy en día las técnicas de adquisición de imágenes tridimensionales son comunes en diversas áreas, pero cabe destacar la relevancia que han adquirido en el ámbito de la imagen biomédica, dentro del cual encontramos una amplia gama de técnicas como la microscopía confocal, microscopía de dos fotones, microscopía de fluorescencia mediante lámina de luz, resonancia magnética nuclear, tomografía por emisión de positrones, tomografía de coherencia óptica, ecografía 3D y un largo etcétera. Un denominador común de todas esas aplicaciones es la constante necesidad por aumentar la resolución y la calidad de las imágenes adquiridas. En algunas de dichas técnicas de imagen tridimensional se da una interesante situación: aunque que cada volumen adquirido no contiene información suficiente para representar el objeto bajo estudio dentro de los parámetros de calidad requeridos por algunas aplicaciones finales, el esquema de adquisición permite la obtención de varios volúmenes que representan diferentes vistas de dicho objeto, de tal forma que cada una de las vistas proporciona información complementaria acerca del mismo. En este tipo de situación es posible, mediante la combinación de varias de esas vistas, obtener una mejor comprensión del objeto que a partir de cada una de ellas por separado. En el contexto de esta Tesis Doctoral se ha propuesto, desarrollado y validado una nueva metodología de proceso de imágenes basada en la transformada wavelet disc¬reta para la combinación, o fusión, de varias vistas con información complementaria de un mismo objeto. El método de fusión propuesto aprovecha la capacidad de descom¬posición en escalas y orientaciones de la transformada wavelet discreta para integrar en un solo volumen toda la información distribuida entre el conjunto de vistas adquiridas. El trabajo se centra en dos modalidades diferentes de imagen biomédica que per¬miten obtener tales adquisiciones multi-vista. La primera es una variante de la micro¬scopía de fluorescencia, la microscopía de fluorescencia mediante lámina de luz, que se utiliza para el estudio del desarrollo temprano de embriones vivos en diferentes modelos animales, como el pez cebra o el erizo de mar. La segunda modalidad es la resonancia magnética nuclear con realce tardío, que constituye una valiosa herramienta para evaluar la viabilidad del tejido miocárdico en pacientes con diversas miocardiopatías. Como parte de este trabajo, el método propuesto ha sido aplicado y validado en am¬bas modalidades de imagen. En el caso de la aplicación a microscopía de fluorescencia, los resultados de la fusión muestran un mejor contraste y nivel de detalle en comparación con cualquiera de las vistas individuales y el método no requiere de conocimiento previo acerca la función de dispersión puntual del sistema de imagen. Además, los resultados se han comparado con otros métodos existentes. Con respecto a la aplicación a imagen de resonancia magnética con realce tardío, los volúmenes fusionados resultantes pre-sentan una mejora cuantitativa en la nitidez de las estructuras relevantes y permiten una interpretación más sencilla y completa de la compleja estructura tridimensional del tejido miocárdico en pacientes con cardiopatía isquémica. Para ambas aplicaciones los resultados de esta tesis se encuentran actualmente en uso en los centros clínicos y de investigación con los que el autor ha colaborado durante este trabajo. Además se ha puesto a libre disposición de la comunidad científica la implementación del método de fusión propuesto. Por último, se ha tramitado también una solicitud de patente internacional que cubre el método de visualización desarrollado para la aplicación de Resonancia Magnética Nuclear. Abstract Nowadays three dimensional imaging techniques are common in several fields, but es-pecially in biomedical imaging, where we can find a wide range of techniques including: Laser Scanning Confocal Microscopy, Laser Scanning Two Photon Microscopy, Light Sheet Fluorescence Microscopy, Magnetic Resonance Imaging, Positron Emission To-mography, Optical Coherence Tomography, 3D Ultrasound Imaging, etc. A common denominator of all those applications being the constant need for further increasing resolution and quality of the acquired images. Interestingly, in some of the mentioned three-dimensional imaging techniques a remarkable situation arises: while a single volume does not contain enough information to represent the object being imaged within the quality parameters required by the final application, the acquisition scheme allows recording several volumes which represent different views of a given object, with each of the views providing complementary information. In this kind of situation one can get a better understanding of the object by combining several views instead of looking at each of them separately. Within such context, in this PhD Thesis we propose, develop and test new image processing methodologies based on the discrete wavelet transform for the combination, or fusion, of several views containing complementary information of a given object. The proposed fusion method exploits the scale and orientation decomposition capabil¬ities of the discrete wavelet transform to integrate in a single volume all the available information distributed among the set of acquired views. The work focuses in two different biomedical imaging modalities which provide such multi-view datasets. The first one is a particular fluorescence microscopy technique, Light-Sheet Fluorescence Microscopy, used for imaging and gaining understanding of the early development of live embryos from different animal models (like zebrafish or sea urchin). The second is Delayed Enhancement Magnetic Resonance Imaging, which is a valuable tool for assessing the viability of myocardial tissue on patients suffering from different cardiomyopathies. As part of this work, the proposed method was implemented and then validated on both imaging modalities. For the fluorescence microscopy application, the fusion results show improved contrast and detail discrimination when compared to any of the individual views and the method does not rely on prior knowledge of the system’s point spread function (PSF). Moreover, the results have shown improved performance with respect to previous PSF independent methods. With respect to its application to Delayed Enhancement Magnetic Resonance Imaging, the resulting fused volumes show a quantitative sharpness improvement and enable an easier and more complete interpretation of complex three-dimensional scar and heterogeneous tissue information in ischemic cardiomyopathy patients. In both applications, the results of this thesis are currently in use in the clinical and research centers with which the author collaborated during his work. An imple¬mentation of the fusion method has also been made freely available to the scientific community. Finally, an international patent application has been filed covering the visualization method developed for the Magnetic Resonance Imaging application.

An ICT-based closed-loop model to improve care for heart failure patients

Durante las últimas décadas se ha producido un fenómeno global de envejecimiento en la población. Esta tendencia se puede observar prácticamente en todos los países del mundo y se debe principalmente a los avances en la medicina, y a los descensos en las tasas de fertilidad y mortalidad. El envejecimiento de la población tiene un gran impacto en la salud de los ciudadanos, y a menudo es la causa de aparición de enfermedades crónicas. Este tipo de enfermedades supone una amenaza y una carga importantes para la sociedad, especialmente en aspectos como la mortalidad o los gastos en los sistemas sanitarios. Entre las enfermedades cardiovasculares, la insuficiencia cardíaca es probablemente la condición con mayor prevalencia y afecta a 23-26 millones de personas en todo el mundo. Normalmente, la insuficiencia cardíaca presenta un mal pronóstico y una tasa de supervivencia bajas, en algunos casos peores que algún tipo de cáncer. Además, suele ser la causa de hospitalizaciones frecuentes y es una de las enfermedades más costosas para los sistemas sanitarios. La tendencia al envejecimiento de la población y la creciente incidencia de las enfermedades crónicas están llevando a una situación en la que los sistemas de salud no son capaces de hacer frente a la demanda de la sociedad. Los servicios de salud existentes tendrán que adaptarse para ser efectivos y sostenibles en el futuro. Es necesario identificar nuevos paradigmas de cuidado de pacientes, así como mecanismos para la provisión de servicios que ayuden a transformar estos sistemas sanitarios. En este contexto, esta tesis se plantea la búsqueda de soluciones, basadas en las Tecnologías de la Información y la Comunicación (TIC), que contribuyan a realizar la transformación en los sistemas sanitarios. En concreto, la tesis se centra en abordar los problemas de una de las enfermedades con mayor impacto en estos sistemas: la insuficiencia cardíaca. Las siguientes hipótesis constituyen la base para la realización de este trabajo de investigación: 1. Es posible definir un modelo basado en el paradigma de lazo cerrado y herramientas TIC que formalice el diseño de mejores servicios para pacientes con insuficiencia cardíaca. 2. El modelo de lazo cerrado definido se puede utilizar para definir un servicio real que ayude a gestionar la insuficiencia cardíaca crónica. 3. La introducción, la adopción y el uso de un servicio basado en el modelo definido se traducirá en mejoras en el estado de salud de los pacientes que sufren insuficiencia cardíaca. a. La utilización de un sistema basado en el modelo de lazo cerrado definido mejorará la experiencia del usuario de los pacientes. La definición del modelo planteado se ha basado en el estándar ISO / EN 13940- Sistema de conceptos para dar soporte a la continuidad de la asistencia. Comprende un conjunto de conceptos, procesos, flujos de trabajo, y servicios como componentes principales, y representa una formalización de los servicios para los pacientes con insuficiencia cardíaca. Para evaluar el modelo definido se ha definido un servicio real basado en el mismo, además de la implementación de un sistema de apoyo a dicho servicio. El diseño e implementación de dicho sistema se realizó siguiendo la metodología de Diseño Orientado a Objetivos. El objetivo de la evaluación consistía en investigar el efecto que tiene un servicio basado en el modelo de lazo cerrado sobre el estado de salud de los pacientes con insuficiencia cardíaca. La evaluación se realizó en el marco de un estudio clínico observacional. El análisis de los resultados ha comprendido métodos de análisis cuantitativos y cualitativos. El análisis cuantitativo se ha centrado en determinar el estado de salud de los pacientes en base a datos objetivos (obtenidos en pruebas de laboratorio o exámenes médicos). Para realizar este análisis se definieron dos índices específicos: el índice de estabilidad y el índice de la evolución del estado de salud. El análisis cualitativo ha evaluado la autopercepción del estado de salud de los pacientes en términos de calidad de vida, auto-cuidado, el conocimiento, la ansiedad y la depresión, así como niveles de conocimiento. Se ha basado en los datos recogidos mediante varios cuestionarios o instrumentos estándar (i.e. EQ-5D, la Escala de Ansiedad y Depresión (HADS), el Cuestionario de Cardiomiopatía de Kansas City (KCCQ), la Escala Holandesa de Conocimiento de Insuficiencia Cardíaca (DHFKS), y la Escala Europea de Autocuidado en Insuficiencia Cardíaca (EHFScBS), así como cuestionarios dedicados no estandarizados de experiencia de usuario. Los resultados obtenidos en ambos análisis, cuantitativo y cualitativo, se compararon con el fin de evaluar la correlación entre el estado de salud objetivo y subjetivo de los pacientes. Los resultados de la validación demostraron que el modelo propuesto tiene efectos positivos en el cuidado de los pacientes con insuficiencia cardíaca y contribuye a mejorar su estado de salud. Asimismo, ratificaron al modelo como instrumento válido para la definición de servicios mejorados para la gestión de esta enfermedad. ABSTRACT During the last decades we have witnessed a global aging phenomenon in the population. This can be observed in practically every country in the world, and it is mainly caused by the advances in medicine, and the decrease of mortality and fertility rates. Population aging has an important impact on citizens’ health and it is often the cause for chronic diseases, which constitute global burden and threat to the society in terms of mortality and healthcare expenditure. Among chronic diseases, Chronic Heart Failure (CHF) or Heart Failure (HF) is probably the one with highest prevalence, affecting between 23 and 26 million people worldwide. Heart failure is a chronic, long-term and serious condition with very poor prognosis and worse survival rates than some type of cancers. Additionally, it is often the cause of frequent hospitalizations and one of the most expensive conditions for the healthcare systems. The aging trends in the population and the increasing incidence of chronic diseases are leading to a situation where healthcare systems are not able to cope with the society demand. Current healthcare services will have to be adapted and redefined in order to be effective and sustainable in the future. There is a need to find new paradigms for patients’ care, and to identify new mechanisms for services’ provision that help to transform the healthcare systems. In this context, this thesis aims to explore new solutions, based on ICT, that contribute to achieve the needed transformation within the healthcare systems. In particular, it focuses on addressing the problems of one of the diseases with higher impact within these systems: Heart Failure. The following hypotheses represent the basis to the elaboration of this research: 1. It is possible to define a model based on a closed-loop paradigm and ICT tools that formalises the design of enhanced healthcare services for chronic heart failure patients. 2. The described closed-loop model can be exemplified in a real service that supports the management of chronic heart failure disease. 3. The introduction, adoption and use of a service based on the outlined model will result in improvements in the health status of patients suffering heart failure. 4. The user experience of patients when utilizing a system based on the defined closed-loop model will be enhanced. The definition of the closed-loop model for health care support of heart failure patients have been based on the standard ISO/EN 13940 System of concepts to support continuity of care. It includes a set of concept, processes and workflows, and services as main components, and it represent a formalization of services for heart failure patients. In order to be validated, the proposed closed-loop model has been instantiated into a real service and a supporting IT system. The design and implementation of the system followed the user centred design methodology Goal Oriented Design. The validation, that included an observational clinical study, aimed to investigate the effect that a service based on the closed-loop model had on heart failure patients’ health status. The analysis of results comprised quantitative and qualitative analysis methods. The quantitative analysis was focused on determining the health status of patients based on objective data (obtained in lab tests or physical examinations). Two specific indexes where defined and considered in this analysis: the stability index and the health status evolution index. The qualitative analysis assessed the self-perception of patients’ health status in terms of quality of life, self-care, knowledge, anxiety and depression, as well as knowledge levels. It was based on the data gathered through several standard instruments (i.e. EQ-5D, the Hospital Anxiety and Depression Scale, the Kansas City Cardiomyopathy Questionnaire, the Dutch Heart Failure Knowledge Scale, and the European Heart Failure Self-care Behaviour Scale) as well as dedicated non-standardized user experience questionnaires. The results obtained in both analyses, quantitative and qualitative, were compared in order to assess the correlation between the objective and subjective health status of patients. The results of the validation showed that the proposed model contributed to improve the health status of the patients and had a positive effect on the patients’ care. It also proved that the model is a valid instrument for designing enhanced healthcare services for heart failure patients.