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Stem cell therapy is an emerging tool to treat a variety of conditions from cancer to musculoskeletal disorders to cardiac disease. Current FDA-approved stem cell therapies utilize cells from peripheral blood or bone marrow to treat patients who have disorders of the hematopoietic system; however clinical trials for utilizing stem cells to treat muscular skeletal disorders and cardiac disease are underway. Because stem cells self‐renew and differentiate in multiple lineage pathways, the general theory behind stem cell therapy is that damaged tissue can be repaired or regenerated and that trophic activity of stem cells can modulate other immune cells. While stem cell therapy has the potential to treat a variety of conditions due to its regenerative and proliferative activity, more study is needed to address ideal injection time, method of injection, distribution, and retention concerns. Imaging stem cells addresses these concerns and can provide more information overall about the fate of stem cells. Contrast agents are needed to increase the contrast and specificity of imaging stem cells. Nanoparticle‐based contrast agents are important tools for imaging because they offer high contrast and stable signal. Chapter 1 of this thesis provides a background on cell therapy and various imaging modalities. Chapter 2 details the design and synthesis of gadolinium-doped synthetic melanin nanoparticles which were used to label stem cells for photoacoustics and magnetic resonance imaging (MRI). Chapter 3 explores the mechanism of ultraviolet (UV)-induced synthetic melanin nanoparticle generation. Chapter 4 describes the design, synthesis, and application of an iron oxide PLGA-based nanoparticle used for ultrasound, photoacoustics, and magnetic particle imaging (MPI). Finally, Chapter 5 describes the synthesis and application of a nanoparticle for cancer treatment that shows an increase in photoacoustic intensity as drug is released. This nanoparticle was then used to treat tumors in mice and luminescence was used to monitor treatment response. Chapter 6 concludes with a perspective on the future of imaging cell therapy with possible directions.

Heart diseases (HDs) are the leading cause of morbidity and mortality worldwide. Despite remarkable clinical progress made, current therapies cannot restore the lost myocardium, and the correlation of genotype to phenotype of many HDs is poorly modeled. In the past two decades, with the rapid developments of human pluripotent stem cell (hPSC) biology and technology that allow the efficient preparation of cardiomyocytes from individual patients, tremendous efforts have been made for using hPSC-derived cardiomyocytes in preclinical and clinical cardiac therapy as well as in dissection of HD mechanisms to develop new methods for disease prediction and treatment. However, their applications have been hampered by several obstacles. Here, we discuss recent advances, remaining challenges, and the potential solutions to advance this field.

Aims Patients with non‐ischaemic dilated cardiomyopathy (DCM) are at increased risk of sudden cardiac death. Identification of patients that may benefit from implantable cardioverter‐defibrillator implantation remains challenging. In this study, we aimed to determine predictors of sustained ventricular arrhythmias in patients with DCM. Methods and results We searched MEDLINE/Embase for studies describing predictors of sustained ventricular arrhythmias in patients with DCM. Quality and bias were assessed using the Quality in Prognostic Studies tool, articles with high risk of bias in ≥2 areas were excluded. Unadjusted hazard ratios (HRs) of uniformly defined predictors were pooled, while all other predictors were evaluated in a systematic review. We included 55 studies (11 451 patients and 3.7 ± 2.3 years follow‐up). Crude annual event rate was 4.5%. Younger age [HR 0.82; 95% CI (0.74–1.00)], hypertension [HR 1.95; 95% CI (1.26–3.00)], prior sustained ventricular arrhythmia [HR 4.15; 95% CI (1.32–13.02)], left ventricular ejection fraction on ultrasound [HR 1.45; 95% CI (1.19–1.78)], left ventricular dilatation (HR 1.10), and presence of late gadolinium enhancement [HR 5.55; 95% CI (4.02–7.67)] were associated with arrhythmic outcome in pooled analyses. Prior non‐sustained ventricular arrhythmia and several genotypes [mutations in Phospholamban (PLN), Lamin A/C (LMNA), and Filamin‐C (FLNC)] were associated with arrhythmic outcome in non‐pooled analyses. Quality of evidence was moderate, and heterogeneity among studies was moderate to high. Conclusions In patients with DCM, the annual event rate of sustained ventricular arrhythmias is approximately 4.5%. This risk is considerably higher in younger patients with hypertension, prior (non‐)sustained ventricular arrhythmia, decreased left ventricular ejection fraction, left ventricular dilatation, late gadolinium enhancement, and genetic mutations (PLN, LMNA, and FLNC). These results may help determine appropriate candidates for implantable cardioverter‐defibrillator implantation.

Myocardial external efficiency is the relation of mechanical energy generated by the left (or right) ventricle to the consumed chemical energy from aerobic metabolism. Efficiency can be calculated invasively, and, more importantly, noninvasively by using positron emission tomography, providing a single parameter by which to judge the adequacy of myocardial metabolism to generated mechanical output. This parameter has been found to be impaired in heart failure of myocardial or valvular etiology, and it changes in a characteristic manner with medical or interventional cardiac therapy. The authors discuss the concept, strengths, and limitations, known applications, and future perspectives of the use of myocardial efficiency.

OBJECTIVES The aims of this study were to evaluate taurine levels in English cocker spaniels with dilated cardiomyopathy and assess their survival time and natural progression of their disease. MATERIALS AND METHODS Retrospective comparison of English cocker spaniels with dilated cardiomyopathy phenotype with and without taurine deficiency at the cardiology department of a UK academic referral centre between 2008 and 2018. RESULTS Taurine plasma concentration was available in 16 English cocker spaniels with dilated cardiomyopathy phenotype; 13 of 16 had congestive heart failure and three of 16 did not. Taurine concentration was low (

Interventional radiology (IR) procedures tend to be complex, which delivers high radiation exposure to patient. In the present study, we measured the radiation exposure dose [Hp(3)] in the eye using a direct eye dosemeter placed next to the physician’s eye during procedures. Physicians wore a direct eye dosemeter just lateral to eyes and an additional direct eye dosemeter outside the radiation protective eyeglasses close to their eyes. Additionally, a neck glass badge was worn at the neck. Although we found a positive correlation between the left neck glass badge dose [Hp(0.07)] and the left eye lens dose [Hp(3)], the value of R2 of the regression equation were 0.62 and 0.71 (outside and inside). We thought that the exact eye lens dose might not be estimated from the neck glass badge. In conclusion, a correct evaluation of the lens dose [Hp(3)] using the direct eye dosemeter is recommended for tachyarrhythmia physicians.

Introduction: Cardiovascular diseases are accompanied by autonomic nervous system (ANS) imbalance which is characterized by decreased vagal tone. Preclinical and clinical studies have revealed that...

[EN]Cardiosphere-derived cells (CDCs) encapsulated within alginate-poly-L-lysine-alginate (APA) microcapsules present a promising treatment alternative for myocardial infarction. However, clinical translatability of encapsulated CDCs requires robust long-term preservation of microcapsule and cell stability, since cell culture at 37 degrees C for long periods prior to patient implantation involve high resource, space and manpower costs, sometimes unaffordable for clinical facilities. Cryopreservation in liquid nitrogen is a well-established procedure to easily store cells with good recovery rate, but its effects on encapsulated cells are understudied. In this work, we assess both the biological response of CDCs and the mechanical stability of microcapsules after long-term (i.e., 60 days) cryopreservation and compare them to encapsulated CDCs cultured at 37 degrees C. We investigate for the first time the effects of cryopreservation on stiffness and topographical features of microcapsules for cell therapy. Our results show that functionality of encapsulated CDCs is optimum during 7 days at 37 degrees C, while cryopreservation seems to better guarantee the stability of both CDCs and APA microcapsules properties during longer storage than 15 days. These results point out cryopreservation as a suitable technique for long-term storage of encapsulated cells to be translated from the bench to the clinic. This work has been supported by the European Union's H2020 Framework Program (H2020/2014-2020) and National Authorities through the Electronic Components and Systems for European Leadership Joint Undertaking (ECSEL JU) program under grant agreement Ecsel-78132-Position-II-2017-IA. The regional Government of Aragon provided L.P. studentship. This research was partially funded by Instituto de Salud Carlos III (PI20/00247) and Agencia Estatal de Investigacion (PID2019-107329RA-C22), cofunded by European Regional Development Fund "A way to make Europe."

Contains fulltext : 225390.pdf (Publisher’s version ) (Open Access) BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (ICD) was designed to avoid complications related to the transvenous ICD lead by using an entirely extrathoracic placement. Evidence comparing these systems has been based primarily on observational studies. METHODS: We conducted a noninferiority trial in which patients with an indication for an ICD but no indication for pacing were assigned to receive a subcutaneous ICD or transvenous ICD. The primary end point was the composite of device-related complications and inappropriate shocks; the noninferiority margin for the upper boundary of the 95% confidence interval for the hazard ratio (subcutaneous ICD vs. transvenous ICD) was 1.45. A superiority analysis was prespecified if noninferiority was established. Secondary end points included death and appropriate shocks. RESULTS: A total of 849 patients (426 in the subcutaneous ICD group and 423 in the transvenous ICD group) were included in the analyses. At a median follow-up of 49.1 months, a primary end-point event occurred in 68 patients in the subcutaneous ICD group and in 68 patients in the transvenous ICD group (48-month Kaplan-Meier estimated cumulative incidence, 15.1% and 15.7%, respectively; hazard ratio, 0.99; 95% confidence interval [CI], 0.71 to 1.39; P = 0.01 for noninferiority; P = 0.95 for superiority). Device-related complications occurred in 31 patients in the subcutaneous ICD group and in 44 in the transvenous ICD group (hazard ratio, 0.69; 95% CI, 0.44 to 1.09); inappropriate shocks occurred in 41 and 29 patients, respectively (hazard ratio, 1.43; 95% CI, 0.89 to 2.30). Death occurred in 83 patients in the subcutaneous ICD group and in 68 in the transvenous ICD group (hazard ratio, 1.23; 95% CI, 0.89 to 1.70); appropriate shocks occurred in 83 and 57 patients, respectively (hazard ratio, 1.52; 95% CI, 1.08 to 2.12). CONCLUSIONS: In patients with an indication for an ICD but no indication for pacing, the subcutaneous ICD was noninferior to the transvenous ICD with respect to device-related complications and inappropriate shocks. (Funded by Boston Scientific; PRAETORIAN ClinicalTrials.gov number, NCT01296022.).

Seizure disorders are associated with multisystem complications. Cardiovascular complications account for a significant proportion of morbidity and mortality in these patients. As such, particular attention must be paid to the incidence of cardiovascular complications especially in populations at increased risk. The background for cardiac dysfunction lies in the interplay of genetic/molecular, autonomic, and iatrogenic factors that contribute to its onset. The purpose of this review was to summarize the state of literature in the last decade with regard to cardiac complications of epileptic seizures in order to increase awareness of short- and long-term debilitating cardiac complications as well as facilitate informed clinical decision-making. Taken together, the evidence provided in this review suggests that cardiac dysfunction following seizures should not be viewed as a separate entity but as an important complication of epileptic seizures. Appropriate cardiac therapy should be instituted in the postictal medical management of epileptic seizures. In acute states, postictal cardiac troponinemia (elevated cTn) should be worked up. Longer-term, monitoring for the development of cardiac structural and functional abnormalities is prudent.

Introducao Ha varios seculos Portugal e Brasil tem uma longa tradicao de cooperacao. Na Medicina, sobretudo na area de Cardiologia, existe um longo historico de colaboracao entre as duas sociedades cientificas – a Sociedade Brasileira de Cardiologia e a Sociedade Portuguesa de Cardiologia – que se estende aos respetivos periodicos. Os Arquivos Brasileiros de Cardiologia ( Arq Bras Cardiol ), publicacao cientifica oficial da Sociedade Brasileira de Cardiologia, com fator de impacto de 1,679 em 2018 (JCR), e a revista [...]

Biomaterials that are commonly used for the attenuation of adverse remodeling or as regenerative treatment for myocardial infarction (MI), often have the capacity to release drugs in a sustained manner, providing strength and stability to the infarcted area, or mimic the extracellular matrix. Retention and redistribution of the injected biomaterials is a factor often overlooked, but plays a significant role in the effectiveness of the treatment. Wash-out of therapeutics from the cardiac area can lead to unwanted side-effects and can therefore add insult to injury. Here, the authors seek a deeper understanding on the mechanisms that play an important role in the retention of injected therapeutics, being: materials, drugs, or a combination thereof. Several factors influencing the therapeutic quantity retained at the target site are discussed; being the timing of injection after MI, cardiac pulsation, and injectate properties such as volume, mechanical properties, and tissue affinity. The importance of understanding is highlighted and these different parameters are taken into. More insight in these parameters can lead to an increase in therapeutic effectiveness, in addition to examination of indirect off-target effects.

Adverse hemodynamics of right ventricular (RV) pacing is known for years. Several studies have revealed that adverse outcomes of RV apical pacing are directly linked to cumulative percentage of ventricular pacing. Algorithms to minimize ventricular pacing are only effective if there is good atrioventricular (AV) conduction. A need for an alternate site for ventricular pacing is evident in patients with high presumed ventricular pacing burden. Most studied alternate site for ventricular pacing is ventricular septum (outflow tract septum and mid-septum). Conventionally septal position of the ventricular pacing lead is confirmed by fluoroscopic appearance of the lead and characteristics electrocardiographic (ECG) features. However, several recent studies have challenged these fluoroscopic and ECG features as to be inadequate. So, there is need for a systematic approach for septal positioning of the ventricular lead.

KEY POINTS A 25-year-old man with a medical history of propionic acidemia was brought to hospital after he collapsed while jogging. He was unresponsive, received immediate bystander cardiopulmonary resuscitation and was defibrillated by paramedics from an initial rhythm of ventricular fibrillation

An important aspect of cell therapy in the field of cardiac disease is safe and effective delivery of cells. Commonly used delivery strategies such as intramyocardial injection and intracoronary infusion both present with advantages and disadvantages. Therefore, alternative delivery routes are explored, such as retrograde coronary venous infusion (RCVI). Our aim is to evaluate safety and efficiency of RCVI by providing a complete overview of preclinical and clinical studies applying RCVI in a broad range of disease types and experimental models. Available data on technical and safety aspects of RCVI are incomplete and insufficient. Improvement of cardiac function is seen after cell delivery via RCVI. However, cell retention in the heart after RCVI appears inferior compared to intracoronary infusion and intramyocardial injection. Adequately powered confirmatory studies on retention rates and safety are needed to proceed with RCVI in the future. Electronic supplementary material The online version of this article (10.1007/s12265-018-9785-1) contains supplementary material, which is available to authorized users.

In this chapter we will discuss the most recent and relevant evidences published in the field of inherited arrhythmogenic disorders, focusing on the so called 'channelopathies' that are associated with sudden cardiac death (SCD) in children: long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT). We will discuss the latest diagnostic criteria for channelopathies released by the European Society of Cardiology, the new data on BrS in children and the recent evidence supporting a genotype-specific therapy for LQTS type 3. Moreover, we will present further insights into the risk stratification of the children affected by LQTS, analyzing the role of imaging for the prediction of life-threatening arrhythmias. In addition, we will offer a perspective on how to deal with genetic results in families affected by SCD at very young ages. The selected publications will aid pediatricians in their clinical work when managing little patients with inherited arrhythmias, providing the most recent information for diagnosis, risk stratification, and management. This work was supported by the Ricerca Corrente of the Italian Ministry of Health. Sí

Background: The use of Cardiovascular Implantable Electronic Devices (CIED), such as the Implantable Cardioverter Defibrillator (ICD) and Cardiac Resynchronization Therapy (CRT), is increasing. The number of leads may vary according to the device. Lead placement in the left ventricle increases surgical time and may be associated with greater morbidity after hospital discharge, an event that is often confused with the underlying disease severity. Objective: To evaluate the rate of unscheduled emergency hospitalizations and death after implantable device surgery stratified by the type of device. Methods: Prospective cohort study of 199 patients submitted to cardiac device implantation. The groups were stratified according to the type of device: ICD group (n = 124) and CRT group (n = 75). Probability estimates were analyzed by the Kaplan-Meier method according to the outcome. A value of p < 0.05 was considered significant in the statistical analyses. Results: Most of the sample comprised male patients (71.9%), with a mean age of 61.1 ± 14.2. Left ventricular ejection fraction was similar between the groups (CRT 37.4 ± 18.1 vs. ICD 39.1 ± 17.0, p = 0.532). The rate of unscheduled visits to the emergency unit related to the device was 4.8% in the ICD group and 10.6% in the CRT group (p = 0.20). The probability of device-related survival of the variable “death” was different between the groups (p = 0.008). Conclusions: Patients after CRT implantation show a higher probability of mortality after surgery at a follow-up of less than 1 year. The rate of unscheduled hospital visits, related or not to the implant, does not differ between the groups. Resumo Fundamento: O uso de dispositivos cardíacos eletrônicos implantáveis (DCEI) como o cardiodesfibrilador (CDI) e terapia de ressincronização cardíaca (TRC) - é cada vez maior. O número de eletrodos de estimulação e desfibrilação varia de acordo com o dispositivo. A colocação do eletrodo no ventrículo esquerdo aumenta o tempo cirúrgico podendo associar-se a maior morbidade no acompanhamento após alta hospitalar, evento muitas vezes confundível com a gravidade da patologia base. Objetivo: Avaliar a taxa de internação não programada na emergência e óbito após cirurgia de dispositivos implantáveis estratificados pelo tipo de aparelho. Métodos: Estudo de coorte prospectivo analisando 199 pacientes submetidos à implante de dispositivos cardíacos. Os grupos foram divididos de acordo com o tipo de dispositivo: CDI (n = 124) e TRC (n = 75). Estimativas de probabilidades foram analisadas pelo método de Kaplan-Meier de acordo com o desfecho. Valor de p < 0,05 foi considerado significativo nas análises estatísticas. Resultados: A maioria da amostra era do sexo masculino (71,9%) - idade média de 61,1 ± 14,2. A fração de ejeção do ventrículo esquerdo foi similar entre os grupos (TRC 37,4 ± 18,1 vs. CDI 39,1 ± 17,0; p = 0,532). A taxa de visita não programada na emergência relacionada ao dispositivo foi de 4,8% no grupo CDI e de 10,6% no grupo TRC (p = 0,20). A probabilidade de sobrevida relacionada ao dispositivo da variável “óbito” mostrou-se diferente entre os grupos (p = 0,008). Conclusões: Paciente após o implante de TRC apresenta maior probabilidade de mortalidade após o procedimento cirúrgico no seguimento menor que 1 ano. A taxa de visita hospitalar não programada, relacionadas ou não ao implante, não difere entre os grupos.

Background Medicine shortages (MS) have become a global concern. It is a real challenge for hospital pharmacists who have to search for possible solutions in order to minimise their impact on patient’s health. Purpose The aim of this study was to assess the MS and to evaluate their effect on a third-level hospital pharmacy (HP) department’s day-to-day activity. Material and methods A retrospective descriptive study was carried out between July 2017 and June 2018. Data were obtained from internal MS data logs and MS notification registers from health authorities (HA). Data collected included: active substance, dosage form, manufacturer, pharmaceutical intervention, if the medicine shortage was informed by HA and if it changed the medicine distribution circuit (from community pharmacy (CP) to HP dispensation). Results One-hundred and fifty-nine MS involving 144 different medicines were recorded during the period of study. Anti-neoplastics (14.5%) and cardiac therapy (10.1%) were the main therapeutic groups affected. In 54 cases (34%) it was necessary to import the active substance. In 43 cases (27%) a controlled medicine distribution programme was initiated to ensure a sufficient supply of medicines to patients. In 26 cases (16.4%) the active substance was purchased from a different manufacturer and in 25 cases (15.7%) a different dosage form was obtained. A therapeutic alternative was used in 11 cases (6.9%), with two of these requiring an importation of a foreign medicine. 35.2% of the MS led to a foreign medicine importation, which represents 26% of our total foreign medicine request applications in a year. According to Spanish law, foreign medicines must be provided by the HP and in 33 cases (20.8%) the medicine distribution circuit changed. One-hundred and eight (67.9%) of the MS registered were informed by HA during the study period. Conclusion MS represent a significant increase in the hospital pharmacist activity, mainly focused on executing administrative tasks and planning for strategies to maintain the medication supply. Furthermore, this problem implies attending new outpatients who usually collect their medication at the CP. The lack of communication of MS supposes a cause of distress for patients, as they are unaware of the current medicine distribution circuit, and a real risk for treatment discontinuation. References and/or acknowledgements No conflict of interest.

Cells release extracellular vesicles (EVs) to communicate in a paracrine manner with other cells, and thereby influence processes, such as angiogenesis. The conditioned medium of human cardiac-derived adherent proliferating (CardAP) cells was recently shown to enhance angiogenesis. To elucidate whether their released EVs are involved, we isolated them by differential centrifugation from the conditioned medium derived either in the presence or absence of a pro-inflammatory cytokine cocktail. Murine recipient cells internalized CardAP-EVs as determined by an intracellular detection of human proteins, such as CD63, by a novel flow cytometry method for studying EV&ndash, cell interaction. Moreover, endothelial cells treated for 24 h with either unstimulated or cytokine stimulated CardAP-EVs exhibited a higher tube formation capability on Matrigel. Interestingly, unstimulated CardAP-EVs caused endothelial cells to release significantly more vascular endothelial growth factor and interleukin (IL)-6, while cytokine stimulated CardAP-EVs significantly enhanced the release of IL-6 and IL-8. By nCounter&reg, miRNA expression assay (NanoString Technologies) we identified microRNA 302d-3p to be enhanced in unstimulated CardAP-EVs compared to their cytokine stimulated counterparts, which was verified by quantitative polymerase chain reaction. This study demonstrates that both CardAP-EVs are pro-angiogenic by inducing different factors from endothelial cells. This would allow to select potent targets for a safe and efficient therapeutic application.

The clinical course of Brugada syndrome (BrS) in children and adolescents is incompletely defined due to the rarity of the phenotype in the first decades of life. In 2007, Probst et al. [(1)][1] reported the outcome of 30 pediatric patients with 3 years of follow-up, who experienced a 3% annual

The heart is a complex organ whose structure and function are intricately linked at multiple length scales. Although several advancements have been achieved in the field of cardiac tissue engineering, current invitro cardiac tissues do not fully replicate the structure or function necessary for effective cardiac therapy and cardiotoxicity studies. This is partially due to a deficiency in current understandings of cardiac tissue organization's potential downstream effects, such as changes in gene expression levels. We developed a novel (to our knowledge) invitro tool that can be used to decouple and quantify the contribution of organization and associated downstream effects to tissue function. To do so, cardiac tissue monolayers were designed into a parquet pattern to be organized anisotropically on a local scale, within a parquet tile, and with any desired organization on a global scale. We hypothesized that if the downstream effects were muted, the relationship between developed force and tissue organization could be modeled as a sum of force vectors. With the invitro experimental platforms of parquet tissues and heart-on-a-chip devices, we were able to prove this hypothesis for both systolic and diastolic stresses. Thus, insight was gained into the relationship between the generated stress and global myofibril organization. Furthermore, it was demonstrated that the developed quantitative tool could be used to estimate the changes in stress production due to downstream effects decoupled from tissue architecture. This has the potential to elucidate properties coupled to tissue architecture, which change force production and pumping function in the diseased heart or stem cell-derived tissues.

Diseases of the cardiac conduction system can be debilitating and deadly. Electronic pacemakers are incredibly effective in the treatment of sinus and AV node dysfunction, yet there remain important limitations and complications. These issues have driven interest in the development of a biological pacemaker. Here, we review experimental progress in animal models and discuss future directions, with a focus on reprogramming endogenous cells in the heart to treat defects of rhythm and conduction.

Patients with pacemakers or implantable cardioverter defibrillators (ICDs) are advised to keep mobile phones at least 6 inches (15 cm) away from these devices to avoid electromagnetic interference. This is because electromagnetic fields emitted by phones can be misinterpreted as intrinsic cardiac