Cardiovascular disease (CVD) claims more lives than any other disease in the world. Although numerous biological pathways share the blame, ventricular tachyarrhythmia (VT) is estimated to account for ~25% of all CVD deaths. A complete understanding of the molecular mechanisms underlying VT is unknown but recent studies have linked VT to improper calcium handling in the heart (canine). The principle calcium regulator in the muscle cell is the calcium ion release channel (aka RyR). Numerous endogenous and exogenous compounds can affect the way the RyR regulates calcium. In particular, abnormal levels of oxidants (reactive oxygen species) can oxidize critical thiol groups on the RyR and modulate its activity. Interestingly, high levels of oxidants are also associated with numerous bodily disease states including cancers, muscle fatigue/failure, and CVD. In this thesis, two important dietary antioxidant compounds, the anthocyanidins pelargonidin and delphinidin, are evaluated for their effects on regulating the transport of calcium through the calcium release channel (RyR1) of the sarcoplasmic reticulum of skeletal muscle. Pelargonidin and delphinidin are structurally similar with delphinidin only differing from pelargonidin by the addition of two hydroxyl groups. Both compounds undergo time dependent structural changes in aqueous solutions at physiological pH and a mixture of more than four structures of each compound can be present in solution simultaneously. Pelargonidin and delphinidin show distinct differences in their calcium flux regulating effect on the RyR1. Delphinidin stimulates calcium flux and RyR1 activity where as pelargonidin can cause both inhibition and stimulation of the RyR1. The strength of stimulation and inhibition of calcium transport through the RyR by delphinidin and pelargonidin may be attributed to the structural and chemical changes in those compounds that occur in solutions near physiological pH and the subsequent chemical characteristics of the diverse set of structures that are simultaneously present in solution.

Introdução: A morte súbita é a principal causa de morte na doença de Chagas, correspondendo de 55 a 65% dos casos. Observa-se que parte destas, ocorre em pacientes com função ventricular esquerda (FEVE) preservada, levando a acreditar que fatores desestabilizadores do substrato arritmogênico exercem um importante papel nestes eventos. Evidências já demonstraram a depressão parassimpática como fator contribuinte na gênese de arritmias diversas em presença de cardiopatia isquêmica. Assim, insiste-se na necessidade de se identificar precocemente quais os pacientes, no contexto da cardiopatia chagásica crônica, apresentam risco aumentado para o desenvolvimento de eventos arrítmicos complexos. Acredita-se que a avaliação autonômica identifique subgrupos distintos de risco. O presente estudo teve como objetivo determinar a sensibilidade do barorreflexo (SBR) em pacientes com doença de Chagas, nas formas indeterminada (GI) e arritmogênica com taquicardia ventricular não sustentada (GII) e com taquicardia ventricular sustentada (GIII) e, secundariamente, avaliar a associação entre a severidade da arritmia ventricular com o grau de comprometimento da SBR. Métodos: 42 pacientes foram submetidos à monitorização cardiovascular não invasiva pelo sistema Task Force ® onde foi determinada a SBR, utilizando o método da fenilefrina e analisada a variabilidade da frequência cardíaca (VFC) no domínio do tempo por meio da eletrocardiografia dinâmica de 24horas e a FEVE, por meio da ecocardiografia. Resultados: Observou-se diferença estatística significativa entre os grupos em relação à SBR em resposta à fenilefrina. O GIII apresentou o menor valor de SBR (6,09 ms/mmHg) quando comparado aos GII (11,84ms/mmHg) e GI (15,23ms/mmHg). Após comparação múltipla entre os grupos, verificou-se diferença significativa entre GI e GIII (p= 0,01). Quando se correlacionou SBR e densidade de extra-sístoles ventriculares (EV), observou-se que todos os pacientes portadores de baixa densidade de EV (< 10/hora) apresentavam SBR preservada (6,1ms/mmHg).Em contrapartida, entre aqueles com alta densidade de EV (>10/hora) somente 59% tinham SBR preservada (p=0,003). Nos pacientes com SBR deprimida (3,0-6,0 ms/mmHg) houve maior densidade de EV (p=0,01). Pacientes com SBR preservada apresentaram tanto função ventricular normal como moderadamente comprometida (66,7% com FEVE<40% e 79,5% com FEVE40%; p=0,62). O mesmo observou-se em pacientes com SBR moderadamente deprimida, (15,4% com FEVE<40% e 33,3% com FEVE40%; p=0,46). Não foi verificada correlação entre SBR e VFC. Ao se aplicar o modelo de regressão logística, observou-se que somente a SBR influenciou o aparecimento da taquicardia ventricular sustentada (p=0.028). Conclusão: A SBR está preservada na forma indeterminada da doença de Chagas e diminuída na forma arritmogênica. O comprometimento da SBR é progressivo e acompanha a evolução da doença, sendo mais intenso nos pacientes com arritmias ventriculares mais complexas. O grau de disfunção autonômica não se correlacionou com a função ventricular, mas, sim, com a densidade e a complexidade das arritmias / Introduction: Sudden death is the main cause of death in Chagas disease, corresponding to 55 to 65% of the cases. Some of these occur in patients with normal or almost normal left ventricular function (LVF), leading us to believe that factors that destabilize the arrhythmogenic substrate play an important role in these events. Evidences show parasympathetic depression to be a contributing factor in the genesis of diverse arrhythmias in the presence of ischemic heart disease. Thus, we insist on the need of an early identification of the patients, in the context of chronic Chagas heart disease, that are at increased risk of developing complex arrhythmic events. It is possible that autonomic assessment allows the identification of distinct risk subgroups. The objective of this study was to determine the baroreflex sensitivity (BRS) in patients with the indeterminate form of Chagas disease, (GI), and with the arrhythmogenic form of Chagas disease with nonsustained ventricular tachycardia (GII) and sustained ventricular tachycardia (GIII) and to assess the correlation between the severity of ventricular arrhythmia and the degree of BRS impairment. Methods: Forty-two patients were subjected to noninvasive cardiovascular monitoring using the Task Force® system. The phenylephrine method was used to determine BRS, 24- hour dynamic electrocardiography was used to analyze heart rate variability (HRV) over time and echocardiography was used to determine LVF. Results: A statistical difference was observed between the groups regarding their BRS to phenylephrine. GIII presented the lowest BRS value (6.09 ms/mmHg) when compared with GII (11.84ms/mmHg) and GI (15.23ms/mmHg). After multiple comparisons among the groups, a significant difference was found between GI and GIII (p=0.01). When BRS was correlated with ventricular extrasystole (VE) density, all patients who had low VE density (<10/hour) had preserved BRS (6.1ms/mmHg). On the other hand, only 59% of those with high EV density (>10/hour) had preserved BRS (p=0.003). In patients with moderately depressed BRS (3.0-6.0 ms/mmHg) there was a greater density of EV (p=0.01). Patients with preserved BRS had preserved or moderately compromised LVF (66.7% with LVF<40% and 79.5% with LVF40%; p=0.62) as had patients with moderately depressed BRS (15.4% with LVF<40% and 33.3% with LVF40%; p=0.46). There was no correlation between BRS and LVF. When the logistic regression model was applied, only BRS influenced the presence of sustained ventricular tachycardia (p=0.028). Conclusion: BRS is preserved in indeterminate Chagas disease and diminished in the arrhythmogenic form. The BRS impairment is progressive as the disease progresses, being more evident in patients with more complex ventricular arrhythmias. The degree of autonomic dysfunction did not correlate with ventricular function but with the density and complexity of the arrhythmias

The aim of this thesis is a diagnosis of ventricular tachycardias, fibrillations and flutters from electrocardiogram. These disturbances of heart rate are ranked among the life threatening arrhytmias. This work presents own method of the automatic detection, which is created for the ECG holter monitoring system. The proposed algorithm is based on the detection in the spectral domain, which is supported by the detection in the time domain. The results show the discrimination of arrhytmias from the normal sinus rhythm and the discrimination from the noise. The method is tested with ECG records from the The AHA Database (American Heart Association) and from The MIT-BIH Malignant Ventricular Arrhythmia Database.

Polymorphic ventricular tachycardia (PVT) is a life-threatening arrhythmia that is typically related to long QT syndrome, organic heart disease, electrolyte abnormalities, cardiotoxic drugs, or adrenergic stimulation. A review of the literature reveals that PVT with normal QT interval and without underlying cause is quite rare. We report a case of idiopathic spontaneous PVT with structurally normal heart and without electrolyte abnormalities, drug reactions, or evidence of catecholamine induced arrhythmia. We also review the literature on the electrocardiographic characteristics and management of idiopathic PVT.

Thesis advisor: Vassilios Bezzerides / The aim of this study was to utilize a massively parallel reporter assay (MPRA) to identify organ-specific microRNA (miRNA) target sequences to refine the timing and expression of transgene expression for gene therapy. We previously had developed a cardiac gene therapy for Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) using a systemically delivered adeno-associated virus (AAV9) vector. We hypothesized that incorporation of organ specific miRNA target sites into our vector construct could improve our therapy’s tissue specificity due to the ability of miRNAs to silence transgene expression. Initially, we attempted to incorporate mir-124 target sequences into our vector to detarget the brain. Although these initial attempts were unsuccessful, the study allowed us to develop a protocol to test the effectiveness of miRNA target sequences. Thereafter, we developed a method to screen thousands of putative miRNA target sequences simultaneously. In this study, target sequences of miRNAs specific to the heart, brain and liver were incorporated into a plasmid library. This plasmid library was subsequently made into AAV and injected into mice from a CPVT transgenic line. Total DNA and RNA was later extracted from the target organs, converted into genomic DNA (gDNA) and complementary DNA (cDNA) libraries respectively, and sent for amplicon sequencing. We analyzed the results using Comparative Microbiome Analysis 2.0 software (CoMA) and a custom python script to count the occurrence of each specified barcode per sample. In doing so, we showed that the miRNA suppression mechanism is not only effective but also organ specific. Furthermore, we developed a second script to create a combinatorial library from a set list of miRNA target sequences enabling us to efficiently test thousands of target sequence combinations at once. In doing so, we will be able to identify effective miRNA target sequence combinations to further improve gene therapy specificity. / Thesis (BS) — Boston College, 2021. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Departmental Honors. / Discipline: Biology.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24878号 / 医博第5012号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 萩原 正敏, 教授 湊谷 謙司, 教授 江藤 浩之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

O sistema Holter é considerado padrão ouro para detecção de arritmias cardíacas, possibilitando o seu diagnóstico e sua relação com os sintomas do paciente. As novas gerações de marcapassos (MP) detectam e registram eletrogramas intracavitários e poderiam dispensar o Holter no seguimento dos pacientes. Os diferentes MP dispõem de algoritmos de detecção de arritmias ventriculares (AV) que variam de acordo com o modelo e sua correlação diagnóstica com Holter foi pouco estudada. O objetivo desse estudo foi avaliar 1. a correlação entre o monitor de eventos dos MP e do Holter na detecção de AV e 2. a concordância das AV detectadas nos dois sistemas. Foram estudados129 pacientes portadores de MP com função de detecção de arritmias, com idade média de 68,6+19.1 anos (entre 19 e 94), 54,8% do sexo feminino. Os pacientes foram submetidos à monitorização com Holter por 72 horas. Assim que o sistema foi ligado, os contadores de eventos dos marcapassos foram reiniciados e os relógios sincronizados, para que ambos os sistemas detectassem os eventos simultaneamente. Os MP foram programados para detecção de eventos com o menor valor de frequência ventricular (FV) e o menor número de batimentos sequenciais (BT) possíveis. Depois de 72 horas, os sistemas Holter foram retirados e os registros analisados, assim como os registros simultâneos dos gravadores dos MP. Foram qualificados como eventos arrítmicos no Holter e MP, respectivamente: EV isoladas e \"PVC\"; extra-sístoles em pares e \"couplets\"; TVNS (> 3BT) e \"triplets\"(3BT), \"runs\"(3 a 8 ou > 8 BT) e \"HVR\" (3 ou 4 BT). As correlações de Spearman foram utilizadas para avaliar se o marcapasso acompanha a detecção dos parâmetros do Holter. Os coeficientes de correlação intraclasse e os respectivos intervalos com 95% de confiança, calculados para avaliar a concordâncias entre os parâmetros equivalentes do marcapasso e do Holter. Foram calculados os coeficientes Kappa para avaliar a concordância na detecção de > 10 \"PVC\"/h com > 10 EV/h. Resultados: Os monitores dos marcapassos subestimaram o Holter. Os registros de \"PVC\", \"triplet\" e \"HVR\" por TVNS apresentaram correlações positivas em relação aos parâmetros do Holter, sendo a mais alta aquela entre \"PVC\" e EV (r=0,501). Porém, a concordância entre os tipos de arritmias detectadas foi baixa (CCI < 0,5), exceção feita à concordância de \"triplet\" com TVNS de três batimentos (CCI=0.984). A concordância na detecção de mais de 10 PVC/h e mais de 10 EV/h foi moderada (kappa= 0,483), embora para os MP da Medtronic, o coeficiente de concordância foi alto (kappa=0.877). Para os MP com algoritmo de detecção de sequências de três batimentos com FV menor que 140bpm ( < 140/3), a correlação entre HVR e TVNS foi expressiva (r = 1), sendo a concordância entre esses parâmetros também bastante alta (CCI = 0,800). Conclusões: A correlação e a concordância na detecção de AV registradas nos MP e no Holter foram inconsistentes. Padronização dos algoritmos de detecção de AV, semelhantes os do sistema Holter, é necessária para que os pacientes portadores de dispositivos implantáveis possam se beneficiar dessa função para seguimento clínico e estratificação de risco / The Holter monitoring is considered the gold standard method for detection of cardiac arrhythmias, enabling its diagnosis and its correlation with the patient\'s symptoms. New generations of artificial pacemakers can detect and record intracavitary electrograms and, theoretically, could discard the Holter during the follow-up of the patients. Pacemakers have different ventricular arrhythmias (VA) detection algorithms, varying according to the model. Their diagnosis capacity comparing to Holter monitoring has been poorly studied. The aim of this study was to evaluate 1. the correlation between the event monitor of the pacemaker and the Holter in VA detection and 2. the agreement between the VA detected in both systems. We studied 129 patients with implanted pacemakers, which had arrhythmia detection function, mean age of 68.6 + 19.1 years (19 to 94), 54.8% female. The patients underwent Holter monitoring for 72 hours. Once the system was connected, event counters of pacemakers were reset and the clocks synchronized, so that both systems could detect the arrhythmic events simultaneously. The pacemakers were programmed to detect events with the lowest ventricular rate and lowest number of sequential beats allowed for each model. After 72 hours, Holter systems were removed and the records analyzed, as well as the simultaneous records of the pacemakers. Were considered as arrhythmic events: PVC isolated (in the pacemaker described as \"PVC\"); premature beats in pairs (pacemaker described as \"couplets\"); NSVT (pacemaker described as \"triplets\"- 3beats, \"runs\"- 4 to 8 or > 8 beats and \"HVR\"- 3 to 4 beats). Spearman rank correlations were used to assess whether the pacemaker and Holter identified the same parameters. The intraclass correlation coefficients and the respective intervals with 95% confidence were calculated to evaluate the concordance between the equivalent parameters of the pacemaker and Holter. Kappa coefficients were calculated to assess the agreement in the detection of > 10 PVC/h by the pacemakers and by the Holter. Results: The pacemakers underestimated the arrhythmias detection of Holter. Records of \"PVC\", \"triplet\" and \"HVR\" by NSVT showed positive correlations with the Holter parameters, and the highest one was among \"PVC\" and EV (r = 0.501). The agreement between the types of arrhythmias detected was quite low (CCI < 0.5), except for \"triplet\" detected by pacemakers and three beats NSVT by Holter (ICC = 0.984). The correlation detection for more than 10 PVC /h was moderate (kappa = 0.483), except for Medtronic pacemakers (kappa=0.877). When the pacemaker was programmed to detect sequences of three beats with heart rate lower than 140bpm ( < 140/3), the correlation between HVR and NSVT was perfect (r = 1) and the agreement between these parameters was also quite high (ICC = 0.800). Conclusions: The correlation and agreement between pacemakers and Holter monitoring in the detection of VA were not consistent. A standardization of the pacemakers\' detection algorithms is necessary before using this function for clinical follow-up and risk stratification of the patients

Estratificar o risco de morte súbita é um grande desafio no manejo da cardiomiopatia hipertrófica (CMH). Os fatores de risco existentes atualmente apresentam baixo valor preditivo positivo e a estratégia para prevenção primária de morte súbita, que é o implante do cardiodesfibrilador implantável (CDI), baseia-se nesses fatores. Estudos que validem novos marcadores de risco são necessários, objetivando identificar pacientes com maior risco de morte súbita. A avaliação da deformação miocárdica (strain) por meio do Speckle Tracking na ecocardiografia bidimensional determina a função regional e global do ventrículo esquerdo, e, ainda, pode se correlacionar à fibrose miocárdica. Objetivo: Avaliar, em portadores de CMH e CDI, se a deformação miocárdica avaliada pelo Speckle Tracking, correlaciona-se com a ocorrência de taquiarritmias ventriculares registradas no monitor de eventos do CDI. Métodos: Foram incluídos 49 pacientes (43,5±15,8 anos; 59% mulheres) portadores de CMH e CDI acompanhados nos ambulatórios de Eletrofisiologia e Miocardiopatias do Instituto Dante Pazzanese de Cardiologia. Todos os pacientes foram submetidos à avaliação ecocardiográfica convencional padrão e análise do strain miocárdico pelo Speckle Tracking bidimensional. Foram divididos em dois grupos: grupo A, composto por aqueles que receberam terapia apropriada pelo CDI ou tiveram apenas a documentação de taquicardia ventricular não sustentada pelo CDI; e grupo B, composto por pacientes sem documentação de arritmias ventriculares no monitor de eventos. As variáveis contínuas foram comparadas utilizando-se testes t de Student pareado ou Mann-Whitney; para as categóricas o teste do x2 ou testes exatos de Fisher. Para análise dos dados, utilizou-se o programa SPSS. Valores de p < 0,05 foram considerados estatisticamente significativos. Resultados: Em 93,9% da população, a indicação do CDI foi por prevenção primária. Quinze pacientes (30,6%) compuseram o grupo A, 10 pacientes, por apresentarem taquicardia ventricular não sustentada (TVNS) e 5 por taquicardia ventricular sustentada (TVS). Os parâmetros ecocardiográficos convencionais não foram diferentes entre os grupos, com exceção do diâmetro da raiz aórtica, maior no grupo A (33,6 ± 4,4 e 29,4 ± 3,5, p = 0,001). Os valores do strain bidimensional longitudinal global, circunferencial global e radial global estavam reduzidos na população, porém não foram estatisticamente diferentes entre os grupos A e B. Pacientes do grupo A tiveram redução significante do strain circunferencial médio ao nível da valva mitral (SC médio VM) e do strain circunferencial no segmento ântero-septal ao nível da valva mitral (SC ântero-septal VM), em relação aos pacientes do grupo B (-12,3 ± 3,2 e -16 ± 3,9, p = 0,041 e -13,6 ± 6,6 e -18,7 ± 7,2, p = 0,039, respectivamente). O SC médio VM >= -14,2% apresentou 84,6% de sensibilidade e 70% de especificidade para predizer a ocorrência de taquicardias ventriculares em portadores de CMH com uma área sob a curva de 0,76 e nível de significância de 0,005; e O SC ântero-septal VM >= -17,9% apresentou 77% de sensibilidade e 60% de especificidade para predizer a ocorrência de taquicardias ventriculares em portadores de CMH com uma área sob a curva de 0,68 e nível de significância de 0,044. Conclusões: A presença de SC médio VM > -14,2% e SC ântero-septal VM > -17,9% correlacionaram-se com a presença de arritmias ventriculares malignas. Houve correlação positiva entre a presença de arritmias ventriculares malignas e o diâmetro da raiz da aorta. / Risk stratification for sudden cardiac death is still a challenging in the management of hypertrophic cardiomyopathy (HCM). The existing risk factors present low positive predictive value, and the strategy for primary prevention of sudden cardiac death, that is the implantable cardioverter-defibrillation (ICD), is based on these factors. Studies to validate new risk markers are necessaries to identify patients with higher sudden cardiac death risk. The evaluation of myocardial deformation (strain) through Speckle Tracking in two-dimensional echocardiography determines the regional and global function of the left ventricle, and still correlate with myocardial fibrosis. Objective: To evaluate, in patients with HCM and ICD, if the myocardial deformation evaluated through the Speckle Tracking correlates with the occurrence of ventricular tachyarrhythmias recorded in the monitor of implantable cardioverter-defribillation events. Methods: Forty-nine patients (mean age, 43,5 ± 15,8; 59% women) with hypertrophic cardiomyopathy and implantable cardioverter-defibrillation followed in Eletrophysiology and Cardiomyopathies Divisions at Dante Pazzanese Institute of Cardiology were included in the study. All patients underwent standard conventional echocardiographic evaluation and analysis of myocardial strain through two-dimensional Speckle Tracking. Patients were divided in two groups: group A, composed of those who received appropriate therapy by the ICD or had only the documentation of ventricular tachycardia not sustained by the ICD; group B, composed of patients without documented ventricular arrhythmias in the event monitor. Continuous variables were compared using paired t-Student test or Mann-Whitney. Categorical variables were analyzed using chi-square test or Fisher exact test. For data analysis, the SPSS program was used. P values < 0.05 were considered statistically significant. Results: Forty-nine patients (mean age, 43,5 ± 15,8; 59% women) were evaluated. 93.9% in the ICD was for Primary Prevention. Fifteen patients comprised the group A, ten patients for presenting Nonsustained Ventricular Tachycardia (NSVT) and five for Sustained Ventricular Tachycardia (SVT). Conventional echocardiographic parameters were not different between the groups, except for the aortic root diameter, higher in group A (33,6 ± 4,4 and 29,4 ± 3,5; p= 0,001). The values of global longitudinal, global circumferential and global radial two-dimensional strain were reduced in the population, but not statistically significant between groups A and B. Patients in group A had a significant reduction of the mean circumferential strain at the level of the mitral valve (mean SC MV) and the circumferential strain at the anteroseptal segment at the level of the mitral valve (anteroseptal MV SC), compared to the patients in group B (-12.3 ± 3.2 and -16 ± 3.9, p = 0.041 and -13.6 ± 6.6 and -18.7 ± 7.2, p = 0.039, respectively). The mean MV SC >= -14.2% presented 84.6% sensitivity and 70% specificity to predict the occurrence of ventricular tachycardias in patients with HCM with an area under the curve of 0.76 and a level of significance of 0.005 and Anteroposterior MV >= -17.9% presented 77% sensitivity and 60% specificity to predict the occurrence of ventricular tachycardias in patients with HCM with an area under the curve of 0.68 and a level of significance of 0.044. Conclusions: The presence of mean circumferential strain at the level of the mitral valve > -14,2% and anteroseptal circumferential strain at the level of the mitral valve > -17,9% correlated with the presence of malignant ventricular arrhythmias. There was a positive correlation between the presence of malignant ventricular arrhythmias and the aortic root diameter.

No description available.