Thesis (M.S.)--University of Michigan, 1978.

Thesis (M.S.)--University of Michigan, 1979.

Background: Biopacemaking is the attempt to replicate sinoatrial node (SAN)-like pacemaker activity in other areas of the heart by manipulating genes involved in pacemaking. Application of this could emulate the electronic pacemaker without the need for implantation of permanent hardware, or directly repair dysfunctional SAN tissue in human disease. We upregulated the transcription factors Tbx18, Tbx3 and the membrane ion exchanger NCX1 in bradycardic subsidiary atrial pacemaker (SAP) tissue which we used as a model of SAN dysfunction. We aimed to show that one or more of these gene targets could improve pacemaker function and alter the molecular character of SAP tissue and thus could potentially be used for the repair of dysfunctional SAN tissue. Methods: SAP tissue was isolated from the right atria of rats and kept beating in culture at 37°C for 48 hours. Recombinant adenoviruses were injected into SAP preparations to upregulate Tbx18, Tbx3 and NCX1 individually. Beating rate, overdrive suppression and pharmacological response to If blockade and β-adrenergic stimulation were measured along with molecular changes in pacemaker and atrial genes and proteins using RT-qPCR and immunohistochemistry. Results: Tbx18 upregulation significantly increased SAP beating rate after 48 hours of culture (a final rate of 141 ± 9 bpm in uninfected SAP tissue versus 215 ± 16 bpm in Ad-Tbx18 infected SAP tissue, p<0.01). It induced upregulation of HCN2 (p<0.01) and RYR2 (p<0.05), downregulation of HCN4 (p<0.05) and no change HCN1, Tbx3, Kv1.5, Kir2.1, Nav1.5, NCX1, Cx43, Cx45, Cav1.2 or Cav3.1. There was also no change in overdrive suppression and no change in response to pharmacology. No increase in beating rate was seen with either Tbx3 or NCX1 upregulation. Tbx3 preparations induced downregulation of the atrial genes Kir2.1 (p<0.01) and Nav1.5 (p<0.05), along with HCN1 (p<0.05), HCN4 (p<0.01), Tbx18 (p<0.05) and NCX1 (p<0.01), upregulated Cx43 (p<0.05) and showed no change in Cx45, RYR2, Kv1.5. NCX1 preparations demonstrated reduced overdrive suppression (p<0.05). Conclusion: Tbx18 showed the most potential for biopacemaking in SAP tissue, however both Tbx3 and NCX1 could be applied as secondary targets to fine tune biopacemaker function. Future work would focus on applying these targets to dysfunctional SAN tissue in larger animals.

A estimulação cardíaca artificial que utiliza o marcapasso cardíaco definitivo é uma das alternativas para o tratamento das arritmias. Entretanto, o uso do marcapasso tem provocado reações singulares e alterações nos hábitos de vida dos portadores, o que, indiretamente, pode afetar sua qualidade de vida. Este estudo teve por objetivo verificar como o paciente portador de marcapasso cardíaco definitivo avalia sua qualidade de vida antes e após o implante do marcapasso. Foram entrevistados 80 pacientes imediatamente antes e após quatro meses de implante. Para avaliação da qualidade de vida, utilizou-se o Índice de Qualidade de Vida (IQV) de Ferrans e Powers: versão cardíaca (1992), que foi traduzido e adaptado para portadores de marcapasso. A maioria dos pacientes era do sexo masculino (65,5%), maior que 61 anos (52,5%) e referiu como principais sintomas falta de ar (62,5%), cansaço (51,3%), tontura (45,0%), precordialgia (42,5%) e dor ou edema nas pernas (41,3%). Os demais sintomas referidos no pré-implante foram palpitação (26,3%), fraqueza (26,3%), síncope / desmaio (21,3%), turgor jugular (5,0%), inapetência / insônia (5,0%), hipertensão / nervosismo /suor frio (5,0%), cefaléia (3,8%). Todos os sintomas regrediram significativamente após o implante, exceto o turgor jugular. Dentre as atividades que deixaram de fazer pós-implante, 25,0% deixaram de pegar peso e 23,3% de trabalhar. O uso de eletrodomésticos foi mantido por 60,0% dos pacientes, 25,0% deixaram de usar ferro elétrico, 13,4% não usam mais chuveiro elétrico e 10,0% não usam mais telefone celular nem ligam a televisão. Os incômodos referidos por serem portadores de marcapasso foram atrapalhar o sono, interferir no trabalho, gerar medo, dor no sítio do gerador e interferência das pessoas na própria vida. As variáveis que mais influenciaram na mudança da qualidade de vida foram as dos Domínios \"Saúde e Funcionamento\" e \"Psicológico / Espiritual\" do IQV. Conclui-se que existe diferença entre a qualidade de vida antes e após o implante de marcapasso cardíaco definitivo, sendo maior, o Índice de Qualidade de Vida após o implante (14,88 versus 17,43) / The artificial cardiac pacing is one of the alternatives for arrhythmias treatment using the permanent cardiac pacemaker. It had provoked some peculiar reactions and changes in the life style of the patients, which can affect their quality of life indirectly. The aim of this study was to verfy how the pacemaker patients evaluate their quality of life before and after the pacemaker implant. It was interviewed 80 patients right before the implant and 4 months after the surgery. It was used the Quality of Life Index: cardiac version of Ferrans & Powers (1992), which was translated and adapted for pacemaker patients. The majority of the patients were male (65,0%), over 61 years old (52,5%) and reported symptoms such as breathless (62,5%), tiredness (51,3%), dizziness (45,0%), precordialgia (42,5%), leg ache or leg edema (41,3%), palpitation (26,3%) and weakness (26,3%). The other symptoms referred were syncope (21,3%), jugular turgor (5,0%), inappetence / sleeplessness (5,0%), hypertension / nervosism / cold sweating (5,0%), cephalea (3,8%). All the symptoms reduced siginificantly, except the jugular turgor. Among the activities they quit after the implant, 25,0% quit carrying heavy things, 23,3% quit their jobs and 31,7% didn´t stop doing anything. The use of house wares was not altered for 60,0% of the patients, 25,0% stopped doing ironing, 13,4% quit taking electric shower and 10,0% neither use cellular phone nor feel confortable in setting TV. The pacemaker patients reported that what most bothered them were the sleep disturbing, the pain in the pacemaker setting, to have fear, the interference in their work and people interference in their own lives. The most influential variables in the quality of life changes were the ones from \"Health and Functioning\" and \"Psychological / Spiritual\" dimensions of the Quality of Life Index. It was concluded that there is difference between the quality of life before and after permanent cardiac pacemaker implant, and the Quality of Life Index is higher after the implant (14,88 versus 17,43)

Many factors affect membrane composition in ectotherms, including allometry, temperature, toxins such as PCB-153, and osmotic stress. This thesis seeks to describe the relationship between membrane composition, size, and phylogeny in twelve species of cypriniform fish; to describe interactions between the homeoviscous responses to temperature and to PCB-153 in goldfish and rainbow trout; and to describe the membrane response to hypoosmotic stress in goldfish. Commonalities in these patterns provide insight into shared mechanisms of phospholipid modulation. In particular, such similarities indicate whether the membrane pacemaker theory of metabolism, which connects allometric relationships between body size, membrane phospholipids, and metabolic rate, can serve as a general framework for understanding membrane composition. Chapter 2 investigates how cypriniform membrane unsaturation decreases with mass through different fatty acid substitutions than in endotherms, but these fatty acids are in turn shown to be due to the species’ relatedness to one another rather than to purely physiological causes. In Chapter 3, PCB-153 is shown to increase cholesterol in liver and brain, while high temperature primarily reduces phospholipid unsaturation. In Chapter 4, these patterns are further explored in trout. As in goldfish, cholesterol modulation is the primary response to PCB-153, whereas temperature primarily reduces phospholipid unsaturation. Trout show more pervasive fatty acid changes than goldfish in all tissues except the liver, which does not respond to PCB exposure, suggesting that PCB-153 pushes trout’s homeoviscous response to a limit that similarly-exposed goldfish do not face. Chapter 5 shows that goldfish intestines decrease membrane saturation; kidneys decrease membrane cholesterol; gills decrease neither; and muscles decrease both in response to long-term exposure to hypoosmotic conditions. The intestine and kidney are both involved in recovering ions from body fluids, but gills suppress ion loss and muscle concentrates ions from the bloodstream. Temperature, osmotic stress, PCB-153, and increasing body size are all addressed via a similar set of membrane responses in fish, which fits with the membrane pacemaker theory’s predictions regarding membrane composition, metabolic rate, and size.

Normal cardiac function is dependent on a healthy conduction system to maintain coordinated and synchronised activity. In the presence of heart failure, dyssynchronous ventricular activation due to left bundle branch block or right ventricular pacing can result in worsening symptoms and increased mortality; cardiac resynchronisation therapy in the form of biventricular pacing has therefore become an established and effective treatment. However, it also appears that right ventricular pacing can be a cause of heart failure in some individuals, even when there is no evidence of associated pre-existing cardiac disease. A better understanding of the processes leading to dyssynchrony-induced cardiomyopathy will allow better identification and treatment of patients who are at risk, and will contribute to our knowledge about heart failure in general. This PhD adopted a translational approach to cardiac dyssynchrony, by developing a novel model of atrial-synchronous ventricular pacing in adult Welsh Mountain sheep. The right ventricle was paced from the apex continuously for 3 months at a rate that was determined by the intrinsic atrial rate; this allowed the ventricular activation pattern to be altered without changing the heart rate. In parallel, a previously-developed model of rapid ventricular pacing was studied. In this model, the heart was paced continuously at a fixed rate of 210 bpm, which led to the development of symptomatic heart failure. In vivo parameters were characterised using standard clinical techniques of electrocardiography and echocardiography. Autonomic nervous system activity was investigated by examining the heart rate responses to pharmacological blockade using atropine and propranolol, and to beta-adrenergic stimulation using dobutamine. Heart rate variability was analysed in the time and frequency domains. In vitro, patch clamping studies were performed on ventricular myocytes isolated through enzymatic digestion from the interventricular septum and left ventricular free wall. Using the perforated patch current clamp technique at 37 C, action potential duration was measured and the associated triggered calcium transient was analysed using the calcium-sensitive fluorescent indicator Fura-2AM.Heart failure was associated with in vivo evidence of autonomic dysfunction, including a 38 % increase in the resting heart rate, blunting of the heart rate response to dobutamine, and almost complete loss of vagal tonic heart rate control. This pattern was not present in dyssynchrony. At a cellular level, normal sheep had heterogeneity of action potential duration, which was longer in the septum than the free wall. Heart failure disrupted this pattern, and was also associated with approximately a 40 % reduction in the magnitude of the calcium transient in both the septum and the free wall. Dyssynchrony was associated with a similar reduction in the calcium transient, but this was isolated to the free wall. RV apical pacing therefore induced a phenotype that resembled a localised cardiomyopathy, but without the associated autonomic dysfunction of the heart failure model. However, it was possible to identify a subgroup within these subjects that displayed a pattern of autonomic changes similar to those seen in heart failure, and this appeared to be associated with the most profound cellular changes. This raises the possibility that early dyssynchrony-induced cardiomyopathy may manifest as changes in the autonomic profile, which may be detectable in clinical practice.

Bakgrund: Att drabbas av en hjärtsjukdom är skrämmande och medför vissa begränsningar för individen. I fall tillståndet kan förbättras av att få en pacemaker implanterad, påverkar detta patienten och des anhöriga på flera olika plan. De främsta anledningarna till att få denna åtgärd är en för långsam puls eller förmaksflimmer. De elektriska impulserna som ska skapa hjärtkontraktionen sprider sig då inte genom hjärtat som den ska. Med hjälp av elektroder som förts ned till hjärtat, tar pacemakern över hjärtats impulsstyrning genom att utlösa en depolarisation vid tillstånd där den normala aktiviteten har upphört eller blivit så inefektiv att det är risk för en cirkulatorisk svikt. En pacemaker botar inte den bakomliggande orsaken till den låga pulsen utan tar enbart bort eller lindrar de fysiologiska symtomen. För en patient är detta en möjlighet till att återfå kraft och fortsätta leva. Syfte: Syftet med denna studie var att belysa personers upplevelse av att leva med pacemaker. Metod: Den valda metoden är en litteraturstudie genom databassökning efter vetenskapliga artiklar, för att kunna se över den kunskap som finns inom ämnet. Resultatet baseras på en granskande resultatanalys av elva vetenskapliga artiklar, funna via sökning i databaserna CINAHL, Pubmed, Google Scholar och Socialogical abstracts. Resultat: Resultatet delades upp i fem huvudteman som representerade fynden i de artiklar som valts att ha med i studien. Dessa var: upplevelse av begränsningar på grund av känslighet för elektromagnetiska fält; upplevelse av förändrad energi och möjlighet till aktivitet; upplevelse av inverkan på det sociala samspelet; upplevelse av en ändrad relation till livet och döden; upplevelse av att förhållandet till kroppen påverkats av pacemakerimplantatet. Slutsats: Att leva med en pacemaker har visat sig vara en stor omställning för många, men det finns även de som inte ser det som något stort. Allas upplevelser är unika men det finns somliga som är återkommande och dessa kan vara bra för vårdpersonal att känna till för att kunna möta patienten i dennes verklighet. / Background: To suffer from a heart disease is frightening and imposes certain restrictions on the individual. In case the condition can be improved by getting a pacemaker implanted, this affects the patient and their relatives on several different levels. The premier reason to have a pacemaker implanted is because of a slow pulse or atrial fibrillation. The electrical impulses that should generate the contraction of the heart do not distribute the impulses. With electrodes connected with wires to the heart, the pacemaker takes over the impulse control of the heart by triggering a depolarization when the normal activity has stopped or is to inenfective for the circulation to be unaffected, which can lead to a circulation failure. The pacemaker does not cure the cause of the slow pulse, but can reset it or moderate the physiological symptoms. For a patient, this is an opportunity to regain power and continue living. Objective: The objective with this study was to illustrate individuals experience living with a pacemaker. Method: The chosen method was a litterature review by searching databases to find scientific articles, to be able to review the knowledge within the matter. The result was based on a review of the results of eleven scientific articles, found by searching the databases CINAHL, Pubmed, Google Scholar and Socialogical abstracts. Results: The results was divided into five themes which represented the findings in the articles chosen for this study, which were: experiencing limitations due to sensitivity to electromagnetic fields; experiencing changes in energy and opportunity to activity; experiencing an impact on social interaction; experiencing a different view to life and death; experiencing the relation to the body has been affected by the pacemaker implant. Conclusion: Living with a pacemaker has been shown to be a major adjustment for many, but there are also those who do not see it as something big. Everyone's experience is unique, but there are some that are recurring and may be useful for health professionals to be aware of in order to meet the patient in his or her reality.

Pacemaker-lead-associated right ventricular perforation is a life-threatening complication. Acute perforation usually presents within 24 hours. Patients with lead perforation are often asymptomatic but fatal complications like hemopericardium, leading to cardiac tamponade and death, are reported. Diagnosis is based on chest x-ray, computed tomography (CT) scan, and echocardiography. The management of the lead perforation is based on clinical presentation. Extraction is avoided in cases of chronic asymptomatic lead perforations because of the associated complications. Urgent intervention is needed in hemodynamically unstable patients with pericardial effusion or cardiac tamponade physiology.

The human body is a well tuned mechanism where systems work in synergy to provide a healthy quality of life. The human circulatory system transports oxygenated blood from the heart to the rest of the body delivering the proper nutrients for cells to function. When the heart malfunctions, serious complications can arise leading to sudden cardiac arrest. Congestive heart failure (CHF) is one heart disease that affects the synchrony of the heart’s ventricles. Cardiac resynchronization therapy (CRT) has been widely accepted as a treatment for CHF. Similar to traditional dual chamber pacing techniques, CRT adds a pacing lead to stimulate the left ventricle. Left ventricular leads are implanted via the coronary sinus which provides the easiest surgical access to the left ventricle. Another option for LV pacing is by using an epicardial lead. This option has proven to be safe and effective but requires major surgery. An epicardial lead is usually implanted by performing a thoracotomy. Many studies have been done to show the benefits of bi-ventricular pacing, therefore developing new methods to gain LV access safely and reliable are highly desirable. The epicardial satellite pacemaker, or EPI pacemaker, is a component of a larger CRT system. This implantable cardiac system is composed of a master pacing unit with leads and a remote satellite pacing unit. The master unit is a traditional CRT device electrically coupled to the right side of the heart. It controls the right atrium and ventricle via transvenous leads anchored to the endocardium of the heart. The master device generates the pacing pulses to stimulate the right atrium and right ventricle and a communications module to transmit pacing commands to the epicardial satellite device. The epicardial satellite pacemaker is a leadless device mounted directly on the epicardium of the left ventricle. The epicardial pacemaker can be implanted using a thoracoscopic procedure during implant of the master unit. In special events, it can be implanted using prophylactic techniques during heart bypass surgery of other surgical procedures where access to the heart is available. Much work needs to be done to prove the technology. But current RF communication capabilities in today’s devices offer the groundbreaking path to develop a satellite LV pacing design.

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