Diagnostic methodology of cardiac dynamics based on the Zipf-Mandelbrot law: evaluation with 50 patients / Metodología diagnóstica de la dinámica cardiaca basada en ley de Zipf-Mandelbrot: evaluación con 50 pacientes

Abstract: Objective: Zipf-Mandelbrot law has been used to assess the complexity of cardiac systems. The objective of this work is to corroborate the clinical applicability of a diagnostic methodology developed from Zipf-Mandelbrot law, in the differentiation of normality and acute cardiac disease. Material and methods: there were taken 50 continuous electrocardiographic Holter monitoring records, 20 normal and 30 with acute alterations of the cardiac dynamics. The frequencies of occurrence of heart rates in ranges of 15 lat/min were organized hierarchically to demonstrate the hyperbolic behavior of dynamics and to apply the Zipf-Mandelbrot law. A linearization was performed and the statistical fractal dimension of each dynamic was obtained, giving rise to the mathematical diagnosis. Sensitivity, specificity and Kappa coefficient were calculated. Results: The values of the statistical fractal dimension of the acute cardiac dynamics were between 0.7123 and 0.9327, whereas for the normal dynamics were found between 0.4253 and 0.6698, evidencing quantitative differences between states of normality and disease. Sensitivity and specificity values of 100% were found and the kappa coefficient was 1. Conclusions: The clinical and diagnostic utility of the mathematical methodology based on Zipf-Mandelbrot law was verified, observing a decrease of dynamics complexity in cases of acute heart disease.(AU)

Resumen: Objetivo: La ley de Zipf-Mandelbrot ha sido utilizada con el fin de evaluar la complejidad de los sistemas cardiacos. El objetivo de este trabajo es corroborar la aplicabilidad clínica de una metodología diagnóstica desarrollada a partir de la ley de Zipf-Mandelbrot, en la diferenciación de normalidad y enfermedad cardiaca aguda. Material y métodos: Se tomaron 50 Holter cardiacos (monitoreo electrocardiográfico continuo ambulatorio), 20 normales y 30 con alteraciones agudas de la dinámica cardiaca. Se organizaron jerárquicamente las frecuencias de aparición de frecuencias cardiacas en rangos de a 15 lat/min, para evidenciar el comportamiento hiperbólico de las dinámicas y aplicar la ley de Zipf-Mandelbrot. Se realizó una linealización y se obtuvo la dimensión fractal estadística de cada dinámica, dando lugar al diagnóstico matemático. Fueron calculadas la sensibilidad, especificidad y el coeficiente Kappa. Resultados: Los valores de la dimensión fractal estadística de las dinámicas cardiacas agudas se encontraron entre 0.7123 y 0.9327, mientras que para las dinámicas normales se hallaron entre 0.4253 y 0.6698, evidenciando diferencias cuantitativas entre estados de normalidad y enfermedad. Se encontraron valores de sensibilidad y especificidad del 100% y el coeficiente kappa fue de 1. Conclusiones: Fue comprobada la utilidad clínica y diagnóstica de la metodología matemática basada en la ley de Zipf-Mandelbrot, observando un decremento de la complejidad de la dinámica en casos de enfermedad cardiaca aguda.(AU)

Cardiomioplastia e artefatos no eletrocardiograma / Cardiomyoplasty and artifacts in the electrocardiogram

Trata-se de uma paciente portadora de insuficiência cardíaca refratária ao tratamento convencional, na qual foi realizada cardiomioplastia do músculo torácico grande dorsal. O músculo era estimulado por marca-passo implantado e os estímulos marcavam no ECG aspectos de artefatos. O ECG se apresenta com os artefatos incidindo sobre o seguimento S-T a cada dois ciclos por segundo, com aspecto inusitado.

A female patient with refractory cardiac failure not respondng to conventional treatment underwent cardiomyoplasty using the latissimus dorsi muscle toimprove cardiac contractions. The muscle was stimuated by an implanted pacemaker with the stimuli presentingaspects of artifacts in the ECG, which registered artifacts in the S-T segment at two cycles per second, with an unsual appearance.

Expression of cardiac function genes in adult stem cells is increased by treatment with nitric oxide agents.

Mesenchymal stem cells (MSCs) have received special attention for cardiomyoplasty because several studies have shown that they differentiate into cardiomyocytes both in vitro and in vivo. Nitric oxide (NO) is a free radical signaling molecule that regulates several differentiation processes including cardiomyogenesis. Here, we report an investigation of the effects of two NO agents (SNAP and DEA/NO), able to activate both cGMP-dependent and -independent pathways, on the cardiomyogenic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) and adipose tissue-derived stem cells (ADSCs). The cells were isolated, cultured and treated with NO agents. Cardiac- and muscle-specific gene expression was analyzed by indirect immunofluorescence, flow cytometry, RT-PCR and real-time PCR. We found that untreated (control) ADSCs and BM-MSCs expressed some muscle markers and NO-derived intermediates induce an increased expression of some cardiac function genes in BM-MSCs and ADSCs. Moreover, NO agents considerably increased the pro-angiogenic potential mostly of BM-MSCs as determined by VEGF mRNA levels.

Asistencia y regeneración del miocardio combinando terapia celular e ingeniería de tejidos. Resultados del estudio clínico MAGNUM / Myocardial regeneration and asistance combined cardiac tissue engineering and stem cell therapy. Outcome of trial MAGNUM

Objetivos. El trasplante celular para la regeneración del miocardio está limitado por la escasa viabilidad del injerto y la baja retención celular. En la miocardiopatía isquémica la matriz extracelular está profundamente alterada, por consiguiente, sería importante asociar un procedimiento para regenerar las células miocárdicas y restaurar la función de la matriz extracelular. En este estudio clínico, fue evaluada la terapia celular intrainfarto asociada a una matriz de colágeno sembrada con células e implantada sobre ventrículos infartados.Métodos. En 15 pacientes (54,2±3,8 años de edad) que presentaban cicatrices miocárdicas postisquémicas en el ventrículo izquierdo (VI) y con indicación de cirugía de revascularización miocárdica, se implantaron, durante la operación, células de la médula ósea mononucleares autólogas (CMO) en la cicatriz. Se agregó sobre esa zona infartada una matriz de colágeno tipo I con el mismo número de CMO

Resultados. No hubo mortalidad ni eventos adversos relacionados (seguimiento 15±4,2 meses). La clase funcional según la New York Heart Association (NYHA) mejoró de 2,3±0,5 a 1,4±0,3 (p=0,005). El volumen de fin de diástole del VI evolucionó de 142±24 a 117±21 mL (p=0,03), el tiempo de desaceleración del llenado del VI mejoró aumentando de 162±7 mseg a 196±8 mseg (p=0,01). El espesor del área cicatrizada progresó de 6±1,4 a 9±1,5 mm (p=0,005). La fracción de eyección (FE) mejoró de 25±7 a 33±5% (p=0,04).Conclusiones. La inyección intramiocárdica de células de médula ósea y la fijación simultánea de una matriz sembrada con progenitores celulares (stem cells) sobre el epicardio fue simple y sin complicaciones. La matriz de colágeno aumento el espesor de la zona del infarto con nuevos tejidos viables, limitando la dilatación ventricular y mejorando la función diastólica. Estos resultados positivos no pueden ser absolutamente relacionados a las células y la matriz, pues se asociaron puentes de revascularización coronaria. En conclusión, la ingeniería de tejidos puede extender las indicaciones y beneficios de la terapia con células madre en cardiología, convirtiéndose en un camino prometedor para la creación de un “miocardio bioartificial”

Objectives. Stem cell therapy for myocardial regeneration is limited by poor graft viability and low cell retention. In ischemic cardiomyopathy the extracellular matrix is pathologically modified, therefore it could be important to associate a procedure aiming at regenerating both, myocardial cells and the extracellular matrix. We evaluated intrainfarct cell therapy associated with a cell-seeded collagen scaffold grafted onto infarcted hearts.Methods. In 15 patients (aged 54.2±3.8 years) presenting LV postischemic myocardial scars and with indication for a single off-pump-CABG, autologous mononuclear bone marrow cells (BMC) were implanted during surgery in the scar. A 3D collagen type I matrix seeded with the same number of BMC was grafted onto the infarction zone.Results. There was no mortality and any related adverse events (follow-up 15±4.2 months). NYHA FC improved from 2.3±0.5 to 1.4±0.3 (p=0.005). LV end-diastolic volume evolved from 142±24 to 117±21 mL (p=0.03), LV filling deceleration time improved from 162±7 ms to 196±8 ms (p=0.01). Scar area thickness progress from 6±1.4 to 9±1.5mm (p=0.005). EF improved from 25±7 to 33±5% (p=0.04).Conclusions. Simultaneous intramyocardial injection of mononuclear bone marrow cells and fixation of a BMC-seeded matrix onto the epicardium is feasible and safe. The cell seeded collagen matrix seems to increase the thickness of the infarct scar with viable tissues and help to normalize cardiac wall stress in injured regions, thus limiting ventricular remodelling and improving diastolic function. Patients’ improvements can not be conclusively related to the cells and matrix due to the association of CABG. Cardiac tissue engineering should extend the indications and benefits of stem cell therapy in cardiology, becoming a promising way for the creation of a “bioartificial myocardium”

Variable timescales of repeated spike patterns in synfire chain with Mexican-hat connectivity.

Repetitions of precise spike patterns observed both in vivo and in vitro have been reported for more than a decade. Studies on the spike volley (a pulse packet) propagating through a homogeneous feedforward network have demonstrated its capability of generating spike patterns with millisecond fidelity. This model is called the synfire chain and suggests a possible mechanism for generating repeated spike patterns (RSPs). The propagation speed of the pulse packet determines the temporal property of RSPs. However, the relationship between propagation speed and network structure is not well understood. We studied a feedforward network with Mexican-hat connectivity by using the leaky integrate-and-fire neuron model and analyzed the network dynamics with the Fokker-Planck equation. We examined the effect of the spatial pattern of pulse packets on RSPs in the network with multistability. Pulse packets can take spatially uniform or localized shapes in a multistable regime, and they propagate with different speeds. These distinct pulse packets generate RSPs with different timescales, but the order of spikes and the ratios between interspike intervals are preserved. This result indicates that the RSPs can be transformed into the same template pattern through the expanding or contracting operation of the timescale.

Transplante celular: nova perspectiva para o tratamento da insuficiência cardíaca / Cell transplantation: a new perspective to heart failure treatment

A despeito da expectativa de alguns autores, o tratamento convencional da insuficiência cardíaca não proporciona regeneração miocárdica. Para isso, o transplante celular ou cardiomioplastia celular poderia representar nova opção de tratamento da insuficiência cardíaca e doença coronária. Células transplantadas em área isquêmica, bem como em cicatrizes de infarto prévio, melhoram a disfunção miocárdica. São necessários novos trabalhos para confirmar esses resultados, entretanto, os resultados disponíveis são promissores. O futuro próximo sinaliza como terapêutica a reconstrução do miocárdio lesado por replicação de cardiomiócitos, transplante ou ativação de células-tronco. O implante local de células da medula óssea autóloga induz angiogênese e melhora áreas isquémicas do miocardio, prevenindo o remodelamento ventricular e melhorando a função cardíaca.

Mesenchymal stem cells and the treatment of cardiac disease.

The ischemia-induced death of cardiomyocytes results in scar formation and reduced contractility of the ventricle. Several preclinical and clinical studies have supported the notion that cell therapy may be used for cardiac regeneration. Most attempts for cardiomyoplasty have considered the bone marrow as the source of the "repair stem cell(s)," assuming that the hematopoietic stem cell can do the work. However, bone marrow is also the residence of other progenitor cells, including mesenchymal stem cells (MSCs). Since 1995 it has been known that under in vitro conditions, MSCs differentiate into cells exhibiting features of cardiomyocytes. This pioneer work was followed by many preclinical studies that revealed that ex vivo expanded, bone marrow-derived MSCs may represent another option for cardiac regeneration. In this work, we review evidence and new prospects that support the use of MSCs in cardiomyoplasty.

Use what you have--biological assistance for the treatment of heart failure in the Caribbean.

Cardiovascular disease represents the main cause of death among adults in the Caribbean. Primary and secondary care facilities are efficiently managed. Cardiac surgical and interventional facilities, however, exist only in a small number of territories and are mainly privately funded and are only accessible to few patients. Patients with end-stage heart failure (ESHF) are given few options apart from palliative care or to seek treatment outside of the region. Transplantation remains the 'gold standard' therapy for ESHF. Establishing a Caribbean cardiac transplantation programme would require legislative and infrastructure changes. Tissue rejection poses a problem and expensive immunosuppressants are needed. Mechanical assist devices are costly and associated with complications such as haemorrhage, thrombosis and infections. Both forms of therapy require significant technical and financial investment and do not appear to be economically viable for the Caribbean. The use of the patient's own skeletal muscle to perform biological cardiac assistance is potentially the ideal alternative. The skeletal muscle is conditioned by electrical stimulation to become fatigue resistant. It is then transposed and harnessed as an auxilliary circulatory pump. The required muscle stimulators are relatively inexpensive and the surgical techniques and postoperative care are not overly demanding. We discuss the financial and research implications of treating patients from the Caribbean who have end-stage heart failure.

Use what you have--biological assistance for the treatment of heart failure in the Caribbean

Cardiovascular disease represents the main cause of death among adults in the Caribbean. Primary and secondary care facilities are efficiently managed. Cardiac surgical and interventional facilities, however, exist only in a small number of territories and are mainly privately funded and are only accessible to few patients. Patients with end-stage heart failure (ESHF) are given few options apart from palliative care or to seek treatment outside of the region. Transplantation remains the 'gold standard' therapy for ESHF. Establishing a Caribbean cardiac transplantation programme would require legislative and infrastructure changes. Tissue rejection poses a problem and expensive immunosuppressants are needed. Mechanical assist devices are costly and associated with complications such as haemorrhage, thrombosis and infections. Both forms of therapy require significant technical and financial investment and do not appear to be economically viable for the Caribbean. The use of the patient's own skeletal muscle to perform biological cardiac assistance is potentially the ideal alternative. The skeletal muscle is conditioned by electrical stimulation to become fatigue resistant. It is then transposed and harnessed as an auxilliary circulatory pump. The required muscle stimulators are relatively inexpensive and the surgical techniques and postoperative care are not overly demanding. We discuss the financial and research implications of treating patients from the Caribbean who have end-stage heart failure

Sequential histologic analysis of the myocardium after dynamic cardiomyoplasty: a study based on right ventricular endomyocardial biopsies.

Although dynamic cardiomyoplasty may promote clinical amelioration and mild improvement in left ventricular function in selected patients, whether cardiac reverse remodeling occurs after the procedure is not clear. We did not find histologic differences among right ventricular endomyocardial biopsy specimens taken before and after the surgery at 3 time periods. This result suggests that the procedure has no effect on the microscopic structure of the right ventricular myocardium. However, because reverse remodeling does not necessarily occur concomitantly in both ventricles, our conclusion cannot be extrapolated to the left ventricular chamber.

Implante intracoronario de células progenitoras de la médula ósea en disfunción ventricular posinfarto por lupus eritematoso sistémico / Intracoronary implant of autologous progenitor cells of bone marrow in ventricular disfunction postinfarct by systemic lupus erythematosus

El caso que se presenta, trata de una paciente con diagnóstico de miocardiopatía isquémica necrótica por lupus eritematoso sistémico con infarto anterolateroapical evolucionado. Por cateterismo intracoronario se implanta, en esta zona muerta, una solución autóloga de médula ósea enriquecida con células progenitoras CD34+. En el seguimiento a los tres meses pudimos comparar restauración de viabilidad en los segmentos comprometidos.

Implante intracoronario de células progenitoras de la médula ósea en disfunción ventricular posinfarto por lupus eritematoso sistémico / Intracoronary implant of autologous progenitor cells of bone marrow in ventricular disfunction postinfarct by systemic lupus erythematosus

El caso que se presenta, trata de una paciente con diagnóstico de miocardiopatía isquémica necrótica por lupus eritematoso sistémico con infarto anterolateroapical evolucionado. Por cateterismo intracoronario se implanta, en esta zona muerta, una solución autóloga de médula ósea enriquecida con células progenitoras CD34+. En el seguimiento a los tres meses pudimos comparar restauración de viabilidad en los segmentos comprometidos. (AU)