Context: Increased physical activity participation and fitness are cardioprotective. The EUROACTION trial demonstrated that a preventive cardiology programme significantly increased self-reported physical activity participation (Wood et al., 2008). Objective: The EUROACTION Physical Activity and Fitness (EPAF) Study aimed to objectively evaluate the effectiveness of the EUROACTION physical activity and exercise intervention at increasing physical activity participation and fitness in people with coronary artery disease (COR) and those at high risk of developing cardiovascular disease (HRI) compared to standard care. Study design: A nested study within a paired cluster randomised controlled trial in eight European countries. Methodology: 12 pairs of centres (12 hospitals and 12 general practices) were randomised to receive the EUROACTION programme (INT) or be monitored for usual care (UC). In the INT hospitals, COR patients participated in a 16-week supervised exercise programme and a home-based activity intervention, delivered by a physiotherapist. In INT general practice nurses were trained to deliver personalised physical activity advice to HRI. Outcome measures: Objective physical activity participation was measured by mean number of steps per day (Yamax Digiwalker SW200 pedometer). Fitness was determined by the Incremental Shuttle Walk Test (ISWT) [hospital centres] and Chester Step Test (CST) [general practice centres]). Results: The mean number of steps in COR patients at 1–year was significantly higher in INT (+2310 steps, 95% CI +1226 to +3394 steps; P=0.003). The difference in cardiorespiratory fitness (ISWT) exceeded the minimal clinically important difference but was not statistically significant (+54 metres [95% CI - 102.8 to +211.0 metres]; P=0.42). In general practice centres, whilst no significant differences were found at 1 year in mean steps per day (+982 steps, 95% CI -569 to +2533 steps) and cardiorespiratory fitness (CST) at 1-year (+0.93 minutes, 95% CI -0.62 to +2.48 minutes), there was a difference in the change over time in fitness in favour of the INT (+0.94 mins [95% CI +0.23 to +1.66 mins]; P=0.02). Marked heterogeneity impacted on statistical power. All differences observed represented clinically important differences. Conclusion: The EPAF-Study has demonstrated that the EUROACTION programme was effective at increasing physical activity participation but objective measures indicate to a lesser degree than the self-reported physical activity outcomes previously published. Clinically important differences in objectively measured physical activity participation and cardiorespiratory fitness suggest further research, which is sufficiently powered, is warranted.

PART I Background: For over forty years, depolarizing, hyperkalemic cardioplegia solutions have served as the standard of care for cardiac surgery. While effective in inducing cardiac arrest, potassium-based solutions are associated with an array of negative consequences, such as coagulopathies, conduction dysfunction, inflammation, coronary vasoconstriction, myocardial edema, and ischemic injury. Adenosine-lidocaine-magnesium, a non-depolarizing, non-potassium-containing solution, has recently entered the clinical arena. Animal research suggests that this agent may provide a method of diastolic arrest that is as effective as potassium-based cardioplegia but with improved protective benefits.Purpose: The aim is to assess the safety and efficacy of adenosine-lidocaine-magnesium as a cardioplegia solution in terms of overall patient outcomes.Methodology: In June 2014, Banner University Medical Center Tucson became the first American institution to adopt the use of PolarShot (ALM)--adenosine-lidocaine-magnesium - as a cardioplegia solution. This one-year, retrospective study compares patients receiving adenosine-lidocaine-magnesium to those receiving high-potassium/low-potassium cardioplegia during adult cardiac surgery. Cases compared in this study include isolated coronary artery bypass, isolated aortic/mitral valve repair/replacement, and combination coronary artery bypass/valve replacement surgery only. A propensity-weighted regression model was used for analysis to determine whether or not cardioplegia treatment affected clinical outcome. To assess overall clinical outcome, major morbidity and mortality and post-procedural length of stay were chosen as primary endpoints. Results: In terms of treatment (adenosine-magnesium-lidocaine vs. high-potassium/low-potassium), no statistically significant difference was found between groups in regard to major morbidity and mortality event occurrences nor was a significant difference found between post-procedural length of stay. Discussion: After comparing postoperative outcomes between cardioplegia treatment groups, PolarShot (ALM) cardioplegia produced postoperative outcomes that were statistically similar to those of high-potassium/low-potassium cardioplegia. The confidence in these results is limited by low case volume, surgical case variability, and retrospective nature of this study. Conclusion: According to this propensity-weighted regression model, PolarShot (ALM) cardioplegia appears to be a safe and effective alternative to traditional potassium-based cardioplegia for the purpose of adult cardiac surgery. More research, including prospective randomized trials, is necessary to confirm or deny the findings of this study. PART II Background: Historically, surgical cardioplegia compounding was accomplished by filling patient-tailored prescriptions on-demand. Modern day compounding has become a manufacturing process to improve quality and accommodate physician demand. Additionally, sterile compounding standards have become more stringent, further necessitating a standardized compounding approach. In 2013, scrutiny of sterile drug compounding increased with passage of the Drug Quality and Security Act (DQSA) and subsequent Federal Drug Administration oversight. This federal mandate requires all compounded sterile preparations distributed by 503B Outsourcing Facilities be tested for potency, stability, and sterility. To accomplish this, compounders must significantly reduce batched formula variability. Purpose: A review of 2014 sales data from a large 503B outsourcing facility and cardioplegia compounder will be conducted. The study will identify solution differences and detail its findings. The aim of this study is to assess cardioplegia variability on a national level. Methodology: Results will be summarized by cardioplegia strategy (Buckberg, high-potassium/low-potassium, crystalloid, del Nido, Adenocaine, and microplegia), dilution strategy (4:1 blood-crystalloid, 8:1 blood-crystalloid, 1:4 crystalloid-blood, all-blood, and all-crystalloid), formula constituents (base solutions, additives, buffers), potassium concentrations. Any observed patterns in formula usage will also be reported, geographical or otherwise. Results / Discussion: Based on institutional use, high-potassium/low-potassium (two-solution) multidose strategy was the most common. Based on solutions ordered, the most common cardioplegia ingredient was potassium chloride, present in almost ninety percent (89.64%) of all units sold. After looking at potassium content, extensive variability was noted in terms of potassium added to the bag (undiluted) and potassium to-be delivered (post-dilutional). Additionally, unique solution formulations identified in multiple institutions were often found in neighboring states or within a single state. Conclusion: The results of this analysis illustrate the extent to cardioplegia formula variability nationwide. Variability exists in both methodology and formulation on a state-to-state, institution-to-institution, even across-single-institution basis. This formula customization appears to be institution- and surgeon-specific, suggesting empirical influence in formula adaptation. Formula standardization may be necessary to combat the compounded issue of formula customization moving forward.

A interconsulta cardiológica corresponde a uma parcela considerável das atividades assistenciais e de ensino do cardiologista, refletindo gasto extra de tempo e recursos. Apesar disso, essa atividade não tem recebido a devida atenção da literatura, com poucos estudos sobre o tema. O objetivo do presente estudo foi, primariamente, comparar a evolução clínica dos pacientes envolvidos na interconsulta cardiológica que tiveram as recomendações seguidas pela equipe médica solicitante (grupo ACEITADOR) com aqueles em que as recomendações não foram seguidas (grupo NÃO ACEITADOR). De forma secundária, procuramos identificar as variáveis determinantes da aceitação das sugestões da equipe cardiológica. Para isso, foi realizado um estudo observacional envolvendo pacientes internados no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, para os quais foram solicitadas interconsultas cardiológicas, no período de março a setembro de 2008. Os dados referentes às interconsultas foram coletados pelo investigador de maneira prospectiva a partir do prontuário dos pacientes. Dentre as 589 interconsultas selecionadas para o estudo, 271 consistiam em avaliações clínicas e 318 avaliações pré-operatórias. Em relação à taxa de aceitação das recomendações cardiológicas, 77% dos pacientes foram classificados no grupo ACEITADOR e 23% classificados no grupo NÃO ACEITADOR. A análise da evolução clínica demonstrou que, dentre os pacientes do grupo NÃO ACEITADOR, 38,8% evoluíram de forma desfavorável (piora clínica ou óbito) contra 5,4% dos pacientes do grupo ACEITADOR (P<0,0001). Após análise de regressão logística, pertencer ao grupo NÃO ACEITADOR (P<0,001; OR 10,25; IC 95% 4,45 - 23,62) e a idade dos pacientes (P=0,017; OR 1,04; IC 95% 1,01 1,07) estiveram associados de forma independente a uma evolução clínica desfavorável. Foram identificados quatro preditores independentes de aceitação das recomendações: a realização de visitas de seguimento (P<0,001; OR 2,43; IC 95% 1,48 4,01), reforço verbal das recomendações (P=0,001; OR 1,86; IC 95% 1,23 2,81), número de recomendações sugeridas (P=0,001; OR 0,87; IC 95% 0,80 0,94) e idade dos pacientes (P=0,002; OR 0,98; IC 95% 0,96 0,99). Portanto, na presente análise, a não aceitação das recomendações da equipe cardiológica por parte da equipe médica solicitante esteve associada a uma evolução clínica desfavorável dos pacientes envolvidos. A realização de visitas de seguimento, reforço verbal, número limitado de recomendações e a menor idade dos pacientes estiveram associados a uma maior aceitação das recomendações da equipe cardiológica / Cardiology referral represents an important part of cardiologist activities, accounting for substantial workload and demanding extra time and resources. Despite the importance of these facts, it has received little attention in the medical literature in the last years. The purpose of this study was to compare the clinical outcome of patients involved in cardiology referral who had the cardiologic recommendations followed by the requesting service (ACCEPTING group) with those whose recommendations were not followed (NON-ACCEPTING group). Secondly, we aimed to determine which of the variables involved in cardiology referral were related to acceptance to consultants recommendations. An observational study was performed at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, involving cardiology consultations during the months of March 2008 through September 2008. Data regarding consultations were prospectively extracted from the medical records by a physician-researcher. Among the 589 cardiology consultations selected for the study, 271 were clinical evaluations and 318 were preoperative evaluations. Regarding compliance of the referring service in following the recommendations offered by cardiology team, 77% of patients were classified in the ACCEPTING group and 23% in the NON-ACCEPTING group. A clinical outcome analysis was performed and showed that 38,8% of patients allocated to NON-ACCEPTING group had evolved unfavorably (clinical deterioration or death) against 5,4% of patients allocated to accepting group (P<0.0001). After logistic regression analysis, belong to NON-ACCEPTING group (P<0.001; OR 10.25; CI 95% 4.45 23.62) and patients age (P=0.017; OR 1.04; CI 95% 1.01 1.07) were variables independently associated to an unfavorable clinical outcome. The multivariate analysis indentified 4 independent predictors of acceptance to consultants recommendations: follow-up notes in the chart (P<0.001; OR 2.43; CI 95% 1.48 4.01), personal communication (P=0.001; OR 1.86; CI 95% 1.23 2.81), number of recommendations (P=0.001; OR 0.87; CI 95% 0.80 0.94) and patients age (P=0.002; OR 0.98; CI 95% 0.96 0.99). Therefore, in this analysis of cardiology referral, a poorer acceptance of cardiologic recommendations was associated to an unfavorable clinical outcome. Follow-up notes in the chart, personal communication, limited number of recommendations and lower patients age were associated to greater acceptance of cardiologic recommendations

Migraines are recurrent debilitating headaches that predominately afflict young women. The pathophysiology of migraines is still not well understood but is related to neurovascular dysfunction. Meningeal blood vessel dilation, extravasation of pro-inflammatory cytokines and activation of trigeminal afferent neurons promote migraine generation. Serotonin (5-HT) is an endogenous vasoactive peptide with diverse physiology. In meningeal blood vessels, serotonin causes vasoconstriction, however in coronary arteries, serotonin causes both vasodilation and vasoconstriction. In diseased coronary arteries, with impaired endothelial function, vasoconstriction predominates. Selective meningeal blood vessel serotonin agonists, termed ‘triptans’, have become the therapy of choice for migraine headaches. However, due to their constrictive effects on the coronary vasculature, triptans are not recommend in patients with known coronary artery disease, patients with greater than one coronary artery risk factor or patients with atherosclerotic cardiovascular disease risk (ASCVD) greater than ten percent. Triptan associated chest pain is a well-known phenomenon. Age, hypertension, dyspepsia, and Raynauds phenomenon are associated with triptan associated chest pain. Hypertension is the strongest risk factor for triptan associated chest pain in males. Although triptan associated chest pain is assumed to be cardiovascular due to its constrictive effect on the coronary vasculature, only a few cases of myocardial infarction, with documented ST elevation and/or troponin elevation, have been reported. Herein we report the case of a male patient with inferolateral ST elevation myocardial infarction, within minutes of receiving subcutaneous sumatriptan for migraine headache. The patient had a normal echocardiogram and electrocardiogram prior to sumatriptan use, and a normal cardiac catheterization afterwards.

Background: During the past 50 years, novel diagnostic tools, interventional approaches, and population-wide changes in the major coronary risk factors have occurred. However, few studies have examined relatively recent trends in the demographic characteristics, clinical profile, and the short-term outcomes of patients hospitalized for acute myocardial infarction (AMI) from the more generalizable perspective of a population-based investigation. Methods:We examined decade long trends (2001 to 2011) in patient’s demographic and clinical characteristics, treatment practices, and hospital outcomes among residents of the Worcester metropolitan area hospitalized with a validated initial AMI (n = 3,730) at all 11 greater Worcester medical centers during 2001, 2003, 2005, 2007, 2009, and 2011. Results:The average age of the study population was 68.5 years and 56.9% were men. Patients hospitalized with a first AMI during the most recent study years were significantly younger (mean age = 69.9 in 2001/03; 65.2 in 2009/11), had lower serum troponin levels, and experienced a shorter hospital stay compared to patients hospitalized during the earliest study years. Hospitalized patients were more likely to received evidence-based medical management practices during the years under study. Multivariable-adjusted regression models showed a considerable decline over-time in the hospital death rate (9.6% in 2001/03; 6.5% in 2009/11), and a significant reduction in the proportion of patients who developed atrial fibrillation, heart failure, and ventricular fibrillation during their acute hospitalization. Conclusions: These results highlight the changing nature of patients hospitalized with an incident AMI, and reinforce the need for surveillance of AMI at the community level.

Non-invasive remote detection of cardiac and blood displacements is an important topic in cardiac telemedicine. Here we propose kinocardiography (KCG), a non-invasive technique based onmeasurement of body vibrations produced by myocardial contraction and blood flow through thecardiac chambers and major vessels. KCG is based on ballistocardiography and seismocardiographyand measures 12 degrees-of-freedom (DOF) of body motion. The integral of kinetic energy (iK)and maximum Power (Pmax) obtained from the linear and rotational SCG/BCG signals, was computedover the cardiac cycle, and used as a marker of cardiac mechanical function. We showedthat KCG metrics show high repeatability, can be computed on 50 Hz and 1 kHz SCG/BCG signalsindifferently, that most of the metrics were highly similar when computed on different sensors,and with less than 5% of error when computed on record length longer than 60 s. Finally, weshow that KCG metrics allow detecting dobutamine-induced haemodynamic changes with a highaccuracy and present a major improvement over single axis ballistocardiography or seismocardiography.These results suggest that KCG may be a robust and non-invasive method to monitorcardiac inotropic activity. / La détection à distance et non invasive des déplacements cardiaques et sanguins est un sujet important en télémédecine. Nous proposons ici la kinocardiographie (KCG), une technique non invasive basée sur mesure des vibrations corporelles produites par la contraction du myocarde et par le flux sanguin au travers des cavités cardiaques et des principaux vaisseaux sanguins. La KCG est basée sur la balistocardiographie et la seismocardiographie et mesure 12 degrés de liberté (DOF) de mouvement corporel. L'intégrale de l'énergie cinétique (iK) et la puissance maximale (Pmax) obtenue à partir des signaux SCG / BCG linéaire et rotationnel, a été calculée au cours du cycle cardiaque, et sont utilisées comme marqueur de la fonction mécanique cardiaque. Ce travail montre que les métriques KCG sont caractérisées par une répétabilité élevée, peuvent être calculées sur des signaux SCG / BCG à 50 Hz et à 1 kHz indifféremment, que la plupart des métriques étaient très similaires lorsqu'elles étaient calculées sur différents capteurs, et avec moins de 5% d'erreur lors du calcul sur une longueur d'enregistrement supérieure à 60 s. Enfin ce travail montre que les métriques KCG permettent de détecter les changements hémodynamiques induits par la dobutamine avec précision et présentent une amélioration majeure par rapport à la balistocardiographie à un seul axe ou à la seismocardiographie. Ces résultats suggèrent que la KCG peut être une méthode robuste et non invasive pour surveiller l'activité inotrope du coeur. / Doctorat en Sciences de l'ingénieur et technologie / La défense publique a eu lieu le 05/05/2021. Cet upload remplace l'upload pécédent et contient les derniers commentaires du jury après la défense publique. / info:eu-repo/semantics/nonPublished

In the heart, sodium (Na+) influx via NaV1.5 channels initiates the action potential, and calcium (Ca2+) influx via CaV1.2 channels has a key role in excitation-contraction coupling and determining the plateau phase of the action potential. Mutations in the genes that encode these ion channels or in proteins that modulate them are linked to arrhythmias and cardiomyopathy, underscoring the need for characterizing mechanisms of regulation. The work presented in this thesis is subdivided into three different chapters, each with a distinct focus on ion channel modulation. The first chapter details our investigation of the functional PKA phosphorylation target for β-adrenergic regulation of CaV1.2. Physiologic β-adrenergic activation of PKA during the sympathetic “fight or flight” response increases Ca2+ influx through CaV1.2 in cardiomyocytes, leading to increased cardiac contractility. The molecular mechanisms of β-adrenergic regulation of CaV1.2 in cardiomyocytes are incompletely known, but activation of PKA is required for this process. Recent data suggest that β-adrenergic regulation of CaV1.2 does not require any combination of PKA phosphorylation sites conserved in human, guinea pig, rabbit, rat, and mouse α1C subunits. To test if any non-conserved sites are required for regulation, we generated mice with inducible cardiac-specific expression of α1C with mutations at both conserved and non- conserved predicted PKA phosphorylation sites (35-mutant α1C). Additionally, we createdanother mouse with inducible cardiac-specific expression of β2 with mutations at predicted PKA phosphorylation sites (28-mutant β2B). In each of these mice, β-adrenergic stimulation of Ca²⁺ current was unperturbed. Finally, to test the hypothesis that redundant functional PKA phosphorylation sites exist on the α1C subunit and β2 subunit or that several sites confer incremental regulation, we crossed the 35-mutant α1C mice with the 28-mutant β2B mice to generate offspring expressing both mutant subunits. In these offspring, intact regulation was observed. These results provide the definitive answer that phosphorylation of the α1C subunit or β2 subunit is not required for β-adrenergic regulation of CaV1.2 in the heart. In the second chapter, we study the influence of calmodulin and fibroblast growth homologous factor (FHF) FGF13 on late Na+ current. Studies in heterologous expression systems show that the Ca²⁺-binding protein calmodulin plays a key role in decreasing late Na⁺ current. The effect of loss of calmodulin binding to NaV1.5 on late Na+ current has yet to be resolved in native cardiomyocytes. We created transgenic mice with cardiac-specific expression of human NaV1.5 channels with alanine substitutions for the IQ motif (IQ/AA), disrupting calmodulin binding to the C-terminus. Surprisingly, we found that the IQ/AA mutation did not cause an increase late Na⁺ current in cardiomyocytes. These findings suggest the existence of endogenous protective mechanisms that counteract the increase in late Na+ current that occurs with loss of calmodulin binding. We reasoned that FGF13, a known modulator of late Na+ current that is endogenously expressed in cardiomyocytes but not HEK cells, might play a protective role in limiting late Na+ current. Finally, we coexpressed the IQ/AA mutant NaV1.5 channel in HEK293 cells with FGF13 and found that FGF13 diminished the late Na⁺ currentcompared to cells without FGF13, suggesting that endogenous FHFs may serve to prevent late Na⁺ current in mouse cardiomyocytes. The third chapter of this thesis focuses on the use of proximity labeling and multiplexed quantitative proteomics to define changes in the NaV1.5 macromolecular complex in Duchenne muscular dystrophy (DMD), in which the absence of dystrophin predisposes affected individuals to arrhythmias and cardiac dysfunction.. Standard methods to characterize macromolecular complexes have relied on candidate immunoprecipitation or immunocytochemistry techniques that fall short of providing a comprehensive view of the numbers and types of interactors, as well as the potential dynamic nature of the interactions that may be perturbed by disease states. To provide an inclusive understanding of NaV1.5 macromolecular complexes, we utilize live-cell APEX2 proximity labeling in cardiomyocytes. We identify several proximal changes that align with the electrophysiological NaV1.5 phenotype of young dystrophin-deficient mice, including a decrease in Ptpn3 and Gdp1l and an increase in proteasomal machinery. Whole-cell protein expression fold-change results were used to reveal the altered global expression profile and to place context behind NaV1.5-proximal changes. Finally, we leveraged the neighborhood- specificity of proteins at the lateral membrane, intercalated disc, and transverse tubules of cardiomyocytes to demonstrate that NaV1.5 channels can traffic to all three membrane compartments even in the absence of dystrophin. Thus, the approach of proximity labeling in cardiomyocytes from an animal model of human disease offers new insights into molecular mechanisms of NaV1.5 dysfunction in DMD and provides a template for similar investigations in other cardiac diseases.

Until now, the role of cyclin dependent kinase 5 (CDK5) in cardiac pathophysiology has not been explored. While CDK5 has been well studied in the neuroscience/Alzheimer’s field as a cyclin-independent kinase, there is currently no investigation into the cardiac-specific role of CDK5. Recently, it was established that inhibition of CDK5 in stem cell derived cardiomyocytes from individuals with Timothy Syndrome (TS) rescued the delayed inactivation phenotype; TS is a fatal genetic long QT syndrome (LQTS) caused by delayed inactivation of the L-type voltage gated Ca2+channel CaV1.2. While it is evident that CDK5 plays an important role in regulating CaV1.2 function, its role in cardiac tissue remains to be elucidated. To determine whether CDK5 is essential for cardiac function, two separate mouse models were established—a cardiac-deficient Cdk5 mouse model (Cdk5 flox x αMHC-MerCreMer+) and a Cdk5 activation mouse model via overexpression of Cdk5’s known activator, p35 (Cdk5r1/p35 OE x αMHC-MerCreMer+). Immediately after spatiotemporal induction of deficiency/activation of Cdk5 in adult mice, echocardiography, histology and proteomic analysis were performed to examine effects on cardiac structure and function. Analysis of cardiac function and morphology in Cdk5 deficient mice revealed severe systolic dysfunction and a dilated cardiomyopathy-like phenotype. These results were further validated by a pathway analysis of quantified global proteome changes. Conversely, mice with an activation of Cdk5 displayed only minor changes in cardiac function with a modest reduction in fractional shortening and ejection fraction. Notably, these mice did not have any significant changes in cardiac chamber morphology, nor any significant changes to their global proteome. Interestingly, however, phosphoproteomic analysis revealed over 3,000 differentially phosphorylated proteins. Pathway and gene ontology analysis of proteome changes revealed significant hits related to cell adhesion. Evidence for the extensively studied role of CDK5 in the brain has demonstrated a critical role for CDK5 kinase activity in the regulation of cell adhesion. Alterations in cell adhesion are observed in a number of cardiac pathologies including heart failure and dilated cardiomyopathy; it is therefore plausible that CDK5 potentially regulates cardiac function via cell adhesion mechanisms. A comparison of the phospho-proteome acutely after Cdk5 depletion vs the phospho-proteome acutely after Cdk5 activation, allowed for the identification of a novel cardiac-specific Cdk5 substrate, beta taxilin (Txlnb). Validation of this potential phospho-substrate with an in situ proximity ligation assay demonstrated the co-localization of Cdk5-Txlnb in wildtype mouse cardiac tissue sections. When looking at co-localization in Cdk5 deficient tissue sections, no signals were observed. Lastly, our lab obtained donor cardiac tissue samples from individuals who passed away due to either heart failure or non-cardiac causes (serving as control cardiac tissue). Analysis of cardiac tissue samples revealed a significant increase in both CDK5 and p35 expression in heart failure samples. Dysregulation of phosphorylation has been implicated in cardiac dysfunction, with known contribution to contractile failure and a number of cardiac pathologies including cardiomyopathies. These findings further support a role for CDK5 in cardiac function. In conclusion, it appears that CDK5 is imperative for the maintenance of healthy cardiac function. Cardiac-specific homozygous and heterozygous Cdk5 deficiency revealed severe systolic dysfunction along with a dilated cardiomyopathy-like phenotype. While the effects of Cdk5 activation in the heart need to be further investigated, initial findings report significant downstream effects on the phosphorylation of a number of proteins, including Txlnb. Moreover, Txlnb was identified as a potential novel cardiac-specific substrate of Cdk5. The importance of identifying a role for CDK5 in the heart extends beyond this study. CDK inhibitors have been at the forefront of drug development for cancer therapeutics and immunotherapy. While modulation of CDK5 activity may be beneficial in one physiological system, it may prove deleterious in another. It is therefore imperative that the full range of molecular and physiological roles of each CDK be fully elucidated prior to therapeutic application. Furthermore, outcomes from this study have the potential to be translational for drug discovery and the development of new therapeutic avenues for heart disease.

Tématem této diplomové práce je design kardiologické gama kamery. Hlavním cílem práce je navrhnout originální, vizuálně i ergonomicky vyvážený design pro sedícího či napůl ležícího pacienta s využitím nejnovějších technologií s důrazem na propojení dílčích segmentů v kompaktní celek.

The standard first aid for a heart attack resulting in cardiopulmonary arrest is effective cardiopulmonary resuscitation (CPR). Chest compressions are most commonly performed on a flat surface with the rescuer kneeling next to the victim with one hand on top of the other on the sternum and elbows straight. This technique of being on the ground may be challenging for those without the mobility and strength to get up and down from the ground. In 2005, the American Heart Association (AHA) Guidelines listed “pedal”, or heel, compression as an acceptable alternative to standard chest compressions (Trenkamp & Perez, 2015). That same year, the recommended depth of a compression increased from 3.8 cm to 5.0 cm (Trenkamp & Perez, 2015). To attain such a depth, extra force and strength arerequired. The heel method may be especially reasonable for those rescuers who cannot attain the floor and those who do not have the cardiovascular or muscular strength to perform traditional chest compressions. The purpose of this study was to evaluate the effects of performance of hands only (HO) versus the combination (CO) of hands only plus pedal CPR on the electrocardiogram, including heart rate and heart rhythm. The subjects utilized in this investigation were six men and nine women between 56 and 71 years of age from San Luis Obispo County in California. Subjects underwent two trials with at least a 15 hour rest period in between but no more than one week. Subjects were randomly assigned to either the Combination (CO) trial or the Hands Only (HO) trial. When they came back for their second trial, they did the trial that they did not do the first time. On average, participants were able to sustain the combination of HO plus pedal CPR longer (9.47 minutes) than they were able to perform standard HO CPR (9.02 minutes) but this difference was not statistically significant (p=0.16). Mean maximum heart rate was 133 ± 23.7 bpm during the CO trial and 125.4 ± 21.9 bpm during the HO trial (p=0.12). Mean percentage of the HR reserve was 75.1% during the CO trial and 61.1% during the HO trial (p=0.09). Mean RPE was not significantly different between CO and HO trials (p=0.2124), nor between genders (p=0.42090). However, for both trials combined the mean RPE was significantly greater at 5 minutes of CPR (4.45 ± 0.53) than at 2 minutes of CPR (3.38 ± 0.31), (p It may take time for individuals to accept pedal CPR as a viable resuscitation method. With the majority of sudden cardiac arrests occurring in the home among older adults in society, it is important to recognize that pedal CPR is an acceptable method and that a rescuer may have this choice if they either need a break from standard CPR or if they can not attain the ground.