Dissertations / Theses on the topic 'Chronic heart failure; Cardiac death'

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Introdução: A insuficiência cardíaca (IC) tem alta morbimortalidade que decorre de fatores causais e refratariedade ao tratamento. A doença renal crônica (DRC) e a anemia têm se associado a pior prognóstico em pacientes com IC grave, especialmente os hospitalizados. Há, porém, poucos estudos que avaliem a prevalência e as conseqüências da DRC e da anemia em pacientes com IC acompanhados ambulatorialmente. Objetivos: Avaliar a prevalência da DRC e anemia e o impacto de desfechos cardiovasculares em portadores de IC sistólica estágios B e C. Pacientes e Métodos: Foram estudados pacientes adultos, com idade >18 anos e diagnóstico de IC sistólica e com fração de ejeção (EF) ≤45%, selecionados do ambulatório do Serviço de Hipertensão, Diabetes e Obesidade do SUS de Juiz de Fora e acompanhados por 12 meses. A anemia foi definida como hemoglobina <12,0g/dl nas mulheres e <13,0g/dl nos homens. A reserva de ferro foi considerada adequada quando índice de saturação da transferrina encontrava-se ≥20% e a ferritina ≥100ηg/dl. A filtração glomerular foi estimada pela fórmula do estudo MDRD e a DRC foi definida como proposto pelo K/DOQI da National Kidney Foundation americana. Considerou-se com desfechos cardiovasculares (CV) a ocorrência de hospitalização e/ou morte decorrente da IC. Os dados demográficos, de exame físico e laboratorial foram obtidos do prontuário dos pacientes. Resultados: Foram avaliados 83 pacientes, com idade média de 62,7±12 anos, sendo 56,6% do sexo feminino. A média da fração de ejeção (FE) foi de 37,8+7,9% e a maioria dos indivíduos (60,2%) estava no estágio C. A prevalência de anemia foi de 24,09%; 30,30% no estágio B e 20% no estágio C. A prevalência de DRC foi elevada, presente em 49,4% da amostra, 42,4% no estágio B da IC e 54% no estágio C. Todos os pacientes com anemia tinham reserva de ferro normal e 68,6% apresentavam DRC concomitante. Os desfechos CV ocorreram em 26,5% da amostra. Na estratificação dos pacientes nos estágios B e C da IC e presença ou não de DRC, evidenciou que 100% e 64,7% apresentaram desfechos, respectivamente. Na análise multivariada, após ajustes para fatores prognósticos no período basal, o diagnóstico de DRC aumentou em 3,6 vezes a possibilidade de desfechos (IC 95%1,04-12,67, p=0,04), enquanto os níveis mais elevados de sódio sérico (R 0,807, IC95%0,862-0,992, p=0,03) e da fração de ejeção (R 0,925, IC95% 0,862-0,942, p= 0,03) se mostraram protetores. Conclusão: Na coorte de pacientes estudada, composta de pacientes com IC estágios B e C, a ocorrência de anemia foi compatível com a observada em outros estudos e com tendência de se associar com menor filtração glomerular. A DRC foi prevalente e independentemente se associou a maior risco de hospitalizações e mortes secundárias à descompensação cardíaca, especialmente nos pacientes assintomáticos.
Introduction: Chronic heart failure (CHF) has a high morbidity and mortality which are consequent to etiologic factors and no response to treatment. Anemia and chronic kidney disease (CKD) have been associated to worse outcome in patients with severe hospitalized CHF. So far, there is few studies that assessed the prevalence and the consequences of anemia and CKD in outpatients with CHF. Aim: To study the prevalence of CKD and anemia and the impact of CV end points in patients with systolic CHF followed in an outpatient clinic. Methods: This is prospective cohort study, dealing with adult patients older than 18 years of age and diagnosis of systolic CHF and ejection fraction (EF) ≤45%, selected from the Hypertension, Diabetes and Obesity Outpatient Clinic of SUS of Juiz de Fora. Anemia was defined as hemoglobin <12,0g/dL in women and <13g/dL in men and women after the menopause. Normal iron store was defined when transferring saturation index was >20% and/or ferritin >100ηg/dL. The glomerular filtration rate was estimated from serum creatinine usinf the MDRD study formula, and CKD was defined as suggested by the K/DOQI of National Kidney Foundation. CV endpoints were defined as death or hospitalization due to CHF, in 12 months follow up. Demographic and clinical date were obtained from the patients’ charts. Results: Eight three patients were studied, the mean age was 62.7±12 years, and 56.6% were female. The EF was 37,8+7,9%, and the majority of the patients had stage C CHF (60,2%). The prevalence of anemia was 24,1%; 30,3% in stage B and 50% in stage C. CKD was diagnosed in 49.4% of the patients, 42,4% of the stage B and 54% in the stage C. All patients with anemia had normal iron storage, and 68,6% had concomitant CKD. Cardiovascular endpoints were observed in 26.5% of the patients. When the sample was stratified in stages B and C of CHF and presence or absence of CKD, it was found that 100% and 64.7% had CV endpoints, respectively. After adjustments for all other prognostic factors at baseline, it was observed that the diagnosis of CKD increased in 3.6 folds the hazard of CV endpoints (CI 95% 1,04-12,67, p=0,04), whereas higher ejection fraction (R 0,925, IC 95% 0,862-0,942, p= 0,03) and serum sodium (R 0,807, IC 95% 0,862-0,992, p=0,03) were protectors. Conclusion: In this cohort of outpatients with CHF stages B and C, the occurrence of anemia was low and frequently associated with concomitant CKD. On the other hand, CKD was prevalent and independently associated with heightened risk for hospitalization and death secondary of cardiovascular causes, mainly in asymptomatic patients.

En France, environ un million de personnes seraient touchées par l’insuffisance cardiaque (IC) ; on recense près de 70 000 décès liés à l’IC, et plus de 150 000 hospitalisations et cela, malgré une prise en charge thérapeutique bien codifiée. Ces chiffres devraient s’accroitre dans les années futures du fait notamment du vieillissement de la population.L’objectif de ce travail était d’étudier l’utilisation des traitements pharmacologiques indiqués dans le traitement de l’IC (beta bloquant, inhibiteur de l’enzyme de conversion, anti-aldostérone, antagoniste des récepteurs à l’angiotensine II, diurétiques, digoxine, ivabradine) en situation réelle de soin, et d’identifier les facteurs cliniques ou pharmacologiques associés à la survenue d’un épisode de décompensation cardiaque.Un premier travail a permis de mesurer la fiabilité des bases de données médico-administratives françaises pour identifier des patients IC.Une deuxième étude a permis d’estimer que 17 à 37% de patients IC n’étaient exposés à aucun traitement de l’IC dans l’année suivant une première hospitalisation pour IC.Les troisième et quatrième parties de cette thèse ont mis en évidence qu’environ un quart des patients IC étaient réhospitalisés dans les 2 ans suivant une première hospitalisation. Les principaux facteurs cliniques prédictifs de cette réhospitalisation étaient l’âge, l’hypertension artérielle, la fibrillation auriculaire et le diabète. L’association retrouvée entre l’utilisation de fer bivalent et la réhospitalisation pour IC, souligne l’importance du risque lié à la présence d’une anémie ou d’une déficience en fer dans la survenue d’un épisode de décompensation cardiaque.Ces résultats permettent de reconsidérer la prise en charge thérapeutique chez les patients IC et mettent en avant la nécessité de renforcer la surveillance des patients les plus à risque de décompenser leur IC
In France, around one million persons would be affected by heart failure (HF); there are nearly 70 000 deaths related to HF and more than 150 000 hospitalizations despite a well defined treatment management. These numbers should increase in the next years due in particular to the ageing of the population.The objective of this work was to study the use of the pharmacological treatments indicated in HF (beta-blocker, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone antagonist, diuretics, digoxin, ivabradine) in real-world setting and to identify the clinical or pharmacological predictors associated with a new episode of cardiac decompensation.A first work has enabled to estimate the accuracy of French claims databases in identifying HF patients.A second study estimated that 17 to 37% HF patients were not exposed to any HF treatment in the year following an incident HF hospitalization.The third and fourth parts of this thesis showed that almost one forth of HF patients was rehospitalized within the 2 years following a first hospitalization. The main clinical predictors of rehospitalization were age, high blood pressure, atrial fibrillation and diabetes. The association found between bivalent iron use and HF rehospitalization underlines the importance of the risk related to anemia or iron deficiency in the occurrence of a cardiac exacerbation episode.These results allow to reconsider the treatment management of HF patients and highlight the need to reinforce the surveillance of patients with a highest risk of cardiac exacerbation

Sudden cardiac death (SCD) risk is reduced by implantable cardioverter defibrillator (ICD) use in appropriately selected patients. Established markers such as impairment of left ventricular function and QRS duration are non specific for arrhythmic death and therefore many patients receive ICD therapy from which they gain no benefit, either due to survival without arrhythmia or death from pump failure. Both myocardial scar and serum protein biomarkers have potential as SCD risk stratifiers, but novel solutions are needed to deliver non invasive tests that are suitable for point of care testing. The aims of this thesis were to explore novel assessment methods for the risk stratification of SCD, with particular focus on heart failure. Several approaches were chosen to explore these concepts: (i) meta-analysis to assess the utility of fragmented QRS, (ii) retrospective evaluation of ECG and CMR to assess ECG markers of repolarisation and (iii) QRS scoring, (iv) prospective evaluation of an automated QRS scoring algorithm to predict myocardial scar, (v) artificial intelligence machine learning techniques to develop and validate an algorithm capable to classifying ECG scar, and (vi) a novel high resolution proteomic technique to propose biomarkers of SCD risk, validated using ELISA (vii). The hypothesis is that novel clinical tools, encompassing technologies and techniques which could stretch across the clinical landscape from primary to specialised care services, can be identified as indicators of ICD benefit in patients at risk of SCD. My results indicate that simpler ECG markers such as T-peak-end, fQRS and QRS scoring have a significant association with myocardial scar, although the strength of association varies according to scar characteristics, and is not specific. The specificity of these markers for mode of death is also weak. Computerised algorithms can serve to speed up manual ECG scoring, whilst maintaining overall accuracy, but greatest potential is seen in using a novel marker, custom developed using artificial intelligence techniques. I also found that candidate serum biomarkers, predictive of death or ventricular arrhythmia, could be identified through high resolution proteomic techniques. Clinical and technical validation with ELISA is possible. Novel non invasive markers, such as serum proteins and computer ECG analysis may be valuable tools to improve risk prediction. The incremental benefit of these tools to determine prognosis, and select those who will most benefit from ICD therapy, can now be addressed by future prospective studies.

There is a growing epidemic of chronic heart failure (CHF) in the developed world. The costs associated with providing care is profound and despite our best efforts, new, more effective treatments for CHF are needed; 50% of patients diagnosed with CHF are dead within 5 years. Current paradigms rely heavily on pharmacologic interventions, which merely help manage the disease. Surgical interventions may also be considered for late stage CHF patients such as heart transplant or left ventricular assist device (LVAD) but require burdensome and invasive surgical procedures. In addition they are costly, and require the need for life long immunosuppressive and anticoagulant therapies respectively. Despite our best intentions, the long-term prognosis for CHF patients remains poor. With over a decade of clinical investigation taken place, data from cell-based therapy trials remains inconsistent. While demonstrating safety, limited efficacy has been reported and to date, no stem cell therapy has been approved by the FDA. Despite these shortcomings important lessons have been learned that can be applied to future developments. Retrospective analysis of early cell-based clinical trial data has suggested that variations in isolated cell number, viability, and potency from donor to donor in autologous preparations yielded wide discrepancies in functional outcomes. In addition, sub culturing adult stem cells, even for short periods of time in 2D polystyrene environments void of complementary cell populations and extra cellular matrix protein interactions, may alter the therapeutic potential of a given cell. As a solution, allogeneic approaches where donor cell quality and potency can be assessed and optimized may help achieve functional benefits. Furthermore, co-dosing with multiple cell populations or developing 3D sub-culture environments that more closely mimic the in vivo milieu may ultimately yield more potent therapeutic cell populations. While these alterations may improve cell-based therapy outcomes, other solutions have been proposed such as tissue engineering. While the concept of tissue engineering is not new, advancements in biomaterials, bioreactor design and cell sources have greatly enhanced the reality of these preparations. Previously, one of the greatest limitations to tissue engineering is overcoming the cell requirements for developing and testing where millions if not billions of cells are required. Cell sourcing limitations appear to have been solved with the discovery and development of induced pluripotent stem cell (iPSC) derived cell populations. First reported in 2007, they have the ability to generate embryonic like pluripotent stem cells without the ethical concerns of embryonic stem cells. These iPSCs hold tremendous potential for drug toxicology / screening, personalized medicine and cell therapies. The body of work described in this dissertation looks at developing and testing a tissue engineered cardiac patch to treat heart failure. For which, an emphasis has been to provide 1) structural support for engrafted cells and 2) a rapidly inducible vascular supply once implanted in vivo. Biomaterials were sourced that facilitate infill by multiple cell populations in 3D culture and the establishment of extra cellular matrix deposits. Together, these patches enhanced cellular development in vitro and result in long term functional improvements in small animal models for CHF. Additional feasibility work was performed in large animal models to permit upscaling and development of surgical implantation techniques to demonstrate clinical applicability

Background - Regular exercise reduces the risk of cardiovascular disease and subsequent sudden cardiac death (SCD). However, a small, but notable proportion of athletes die suddenly due to inherited or congenital disorders of the heart that predispose to malignant ventricular arrhythmias. Such tragedies are highly publicised, particularly when high-profile athletes are involved. To date, limited evidence for the efficacy of cardiovascular pre-participation screening exists outside of the Italian experience. Furthermore, limited data exists examining the impact of ethnicity on cardiac adaptations to physical training. Whilst the cardiovascular benefits of exercise are well known, the impact of life-long endurance exercise is less well understood. Long term high-intensity endurance exercise is associated with changes in cardiac morphology together with electrocardiographic alterations that are believed to be physiologic in nature. Recent data however, has suggested a number of deleterious adaptive changes in cardiac structure, function and electrical activity in response to life-long endurance activity. Aims and Objectives - The aims of this PhD were; 1) To find an effective preparticipation screening method that would successfully identify pre-existing cardiovascular abnormalities, 2) To identify the prevalence of hypertrophic cardiomyopathy and Long QT syndrome in elite UK athletes; 3) To examine the impact and significance of ethnicity upon left ventricular remodelling in elite athletes, and 4) To examine the acute and chronic impact of ultra-endurance exercise across the life-span in male endurance athletes. Major Results and Conclusions – 1) Study 2 sought to confirm the efficacy of resting 12-Lead ECG ‘alongside’ personal/family history questionnaires and physical examinations as collective tools to identify diseases that have the potential of causing sudden death within a cohort of elite junior athletes (n=1074) and physically active school children (n=1646). Nine participants were identified with a positive diagnosis of a disease associated with SCD. None of those diagnosed with a disease associated with SCD were symptomatic or had a family history of note. Thus, personal symptoms and family history questionnaires alone are inadequate in the identification of individuals with diseases associated with SCD. In conclusion, resting 12-Lead ECG is paramount when screening for diseases that have the potential of causing sudden death in the young. 2) Study 3 examined 3,500 asymptomatic elite athletes (75% male) with a mean age of 20.5 ± 5.8 years with 12-lead ECG and 2-dimensional echocardiography. None had a known family history of HCM. Of the 3,500 athletes, 53 (1.5%) had LVH (mean 13.6 ± 0.9mm, range 13 to 16mm), and of these 50 had a dilated LV cavity with normal diastolic function to indicate physiological left ventricular hypertrophy. Three (0.08%) athletes with LVH had a non-dilated LV cavity and associated deep T-wave inversion that could have been consistent with HCM. However, none of the 3 athletes had any other phenotypic features of HCM on further non-invasive testing and none had first-degree relatives with features of HCM. In conclusion, the prevalence of HCM in elite athletes is significantly less than in the general population; with the demands of strenuous exercise on the cardiovascular system selecting out most individuals with HCM. Study 4 examined 2000 elite athletes in order to identify the prevalence of Long QT syndrome. Three athletes had a QTc value of >500 ms and all exhibited one of: paradoxical prolongation of QTc during exercise, a confirmatory genetic mutation, or prolonged QTc in a first-degree relative. In contrast, none of the athletes with a QTc value of <500 ms had any other features to indicate LQTS. Accordingly, the prevalence of a prolonged QTc interval in elite British athletes is 0.4%. 3) Study 6 examined 300 nationally ranked UK black male athletes (mean age 20.5 years) in comparison to 150 black and white sedentary individuals and 300 highly-trained white male athletes. Black athletes exhibited greater LV wall thickness and cavity size compared with sedentary black and white individuals. Black athletes had greater LV wall thickness compared with white athletes. A minority of black athlete’s exhibit LVH ≥15 mm; proposing that in the absence of cardiac symptoms or a family history of HCM, an LV wall thickness ≥15 mm in black athletes may represent physiologic LVH when the LV cavity is enlarged and diastolic indexes are normal. 7 black athletes (12%) with LVH displaying deep T-wave inversions in leads V1 to V4. In conclusion, in the absence of obvious pathology, these electrical anomalies in black athletes likely represent a normal spectrum of ECG changes in response to physical training. 4) Study 8 examined 17 male participants (age 33.5 ± 6.5 years, 26–40 years) using cardiac magnetic resonance (CMR) and echocardiography before and after a marathon to investigate the relationship between systolic function and diastolic function against biomarkers of cardiac damage. Results demonstrates biomarkers of myocardial cell damage following an acute bout of prolonged exercise are not associated with either systolic or diastolic functional measures, and do not seem to be associated with any detectable myocardial inflammation, oedema, or scarring using either gold standard techniques of gadolinium enhanced CMR or echocardiography respectively. The impact of multiple episodes of prolonged exercise, as experienced by highly trained veteran endurance athlete is not fully understood. 5) Study 10 examined the cardiac structure and function of 12 life-long, competitive endurance veteran athletes (> 50 yrs, mean ± SD marathons 178 ± 209 (range 20 – 650)) against 17 young male endurance athletes (<40 yrs) using echocardiography and CMR with late gadolinium enhancement (LGE) to assess myocardial fibrosis. Lifelong veteran athletes had smaller LV and RV end-diastolic and end-systolic volumes (p<0.05) but maintained LV and RV systolic function compared with young athletes. In 6 (50%) of the veteran athletes LGE of CMR indicated the presence of myocardial fibrosis; no LGE in the young athletes. The prevalence of LGE in veteran athletes was not associated with the number of competitive marathons or ultra-endurance marathons (>50 miles) completed, age, LV and RV end-diastolic volumes or LV mass (p>0.05). In conclusion, there is limited evidence at present demonstrating that cardiovascular re-modelling following lifelong endurance exercise leads to long-term disease progression, cardiovascular disability or SCD.

Given that chronic hyperglycemia generates toxic methylglyoxal, the detoxifying effect of glyoxalase-1 (Glo1) on chronic hyperglycemia induced explant-derived cardiac stem cell (EDC) dysfunction was investigated. Wildtype (WT) and Glo1 over-expressing (Glo1TG) mice with or without streptozotocin treatment were studied. Hyperglycemia reduced overall culture yields while increasing the reactive dicarbonyl content within WT mice. These intrinsic cell changes reduced the angiogenic potential and nanoparticle production by hyperglycemic EDCs while promoting cell senescence. Compared to transplant of normoglycemic WT EDCs, hyperglycemic EDCs reduced myocardial function following infarction by inhibiting angiogenesis and endogenous repair mechanisms. In contrast, EDCs from hyperglycemic Glo1TG mice decreased reactive dicarbonyl content and restored culture yields. Intramyocardial injection of hyperglycemic Glo1TG EDCs also boosted myocardial function and reduced scarring. These findings demonstrate that, while chronic hyperglycemia decreases the regenerative performance of EDCs, over-expression of Glo1 reduces dicarbonyl stress and rescues the adverse effects of hyperglycemia on EDCs.

Thesis (Ph.D.) - University of Glasgow, 2008.
Ph.D. thesis submitted to the Faculty of Medicine, Division of Cardiovascular and Medical Sciences, University of Glasgow, 2007. Includes bibliographical references. Print version also available.

Biomedical Sciences
Ph.D.
The high metabolic demand of the heart makes it essential that an efficient and tightly controlled system be in place to regulate energy production. Contractility is mediated by a variable flux in intracellular calcium (iCa2+), which is proposed to be integrated into mitochondria to regulate cardiac energetics. Moreover, mitochondrial Ca2+ (mCa2+)-overload is known to activate the mitochondrial permeability transition pore (MPTP) and induce cell death. However, the true function of cardiac mCa2+ in physiology remains unknown. Recent studies have reported that the Mcu gene encodes the channel-forming portion of the mitochondrial calcium uniporter (MCU) and is required for mCa2+ uptake (Baughman et al., 2011; De Stefani, Raffaello, Teardo, Szabo, & Rizzuto, 2011). To examine the role of mCa2+ in the heart, we generated a conditional, cardiac-specific knockout model and deleted Mcu in adult mice (Mcu-cKO). Loss of Mcu protected against myocardial ischemia-reperfusion (IR) (40 min occlusion of the left coronary artery (LCA) followed by 24h reperfusion) injury by preventing the activation of the MPTP. We observed a 45% reduction in infarct size per area-at-risk and a 65% reduction in cardiac troponin-I serum levels from 24h post-IR. In addition, while we found no baseline phenotype or change in baseline mCa2+ content, Mcu-cKO mice lacked contractile responsiveness to β-adrenergic receptor stimulation (isoproterenol infusion) as assessed by invasive hemodynamics, and, in parallel, were unable to activate mitochondrial dehydrogenases, thereby decreasing tricarboxylic acid (TCA) cycle flux and cardiac NADH. We found that Mcu-cKO mice had a 3-fold increase in pyruvate dehydrogenase (PDH) phosphorylation and a 50% decrease in PDH activity post-isoproterenol infusion. Further experimental analyses in isolated adult cardiomyocytes confirmed a lack of energetic responsiveness to acute sympathetic stress (isoproterenol failure to mediate an increase in oxidative phosphorylation capacity) supporting the hypothesis that the physiological function of the MCU in the heart is to modulate Ca2+-dependent metabolism during the ‘fight or flight’ response. However, questions still remain on how basal mCa2+ levels are regulated and if it contributes to cardiac disease. The mitochondrial sodium/calcium exchanger (mNCX) is hypothesized as the primary mechanism of mCa2+ efflux, but to date no study has confirmed its identity or function in an in vivo system (Palty et al., 2010). To investigate the role of mNCX in the heart, we generated mutant mice with loxP sites flanking exons 5-7 of the candidate gene, Slc8b1, and crossed them with a tamoxifen-inducible, cardiomyocyte-specific, αMHC-Cre mouse to delete mNCX in the adult heart (mNCX-cKO). Biophysical study of cardiomyocytes isolated from mNCX-cKO mice revealed a significant reduction in mCa2+ efflux rate. Tamoxifen-induced deletion of Slc8b1 in adult hearts caused sudden death with less than 15% of mice surviving after 10 days. Echocardiographic evaluation of mNCX-cKO hearts 3d post-tamoxifen revealed significant left ventricular (LV) remodeling, characterized by significant dilation and a substantial decrease in function. In addition, mNCX-cKO hearts exhibited increased reactive oxygen species generation when assessed by DHE imaging of live myocardial tissue and mitoSOX Red imaging in isolated adult cardiomyocytes. Using an Evan’s blue dye exclusion technique, we found that mNCX-cKO hearts displayed significant sarcolemmal rupture (~8% of all myocytes at a single time point 3d post-tamoxifen), indicative of cellular necrosis. To rescue the sudden death phenotype and acute loss of cells, we crossed our mNCX-cKO mice with the cyclophilin d (a mediator of MPTP-opening) knockout mice. mNCX-cKO x CypD-KO mice had a significant improvement in survival and LV-function. In addition, loss of MPTP activation also rescued mitochondrial pathology on the subcellular level. Since deletion of mNCX was detrimental on cardiac function, we thought that increasing mNCX could protect cardiomyocytes by reducing mCa2+-overload during cardiac disease. To test this, we generated a conditional, cardiac-specific mNCX overexpression mouse model (mNCX-Tg) to assess if increasing mCa2+ efflux would prevent cardiac injury in multiple pathological surgical models. mNCX-Tg and controls were subjected to in vivo IR injury followed by 24h reperfusion and myocardial infarction (MI) (permanent LCA ligation). mNCX-Tg mice displayed reduced cell death (a 43% reduction in infarct size 24h post-IR and a 33% reduction in scar size 4w post-MI), preserved LV function, a reduction in ROS generation, and a decrease in numerous HF indices. For the first time, we showed that mNCX is essential for maintenance of the mCa2+ microdomain in cardiomyocytes and that mNCX represents a novel therapeutic target in HF.
Temple University--Theses

Physiology
Ph.D.
Myocardial infarction (MI) leads to heart failure (HF) and premature death. The respective roles of myocyte death and depressed myocyte contractility in the induction of HF after MI have not been clearly defined. Cardiac ryanodine receptor (RyR2) has been linked to cardiac arrhythmias and HF. It has been controversial that protein kinase A (PKA) hyperphosphorylation of the RyR2 at a single residue, Ser-2808 is a critical mediator of progressive cardiac dysfunction after MI. We developed two mouse models. In one model with beta2a (LTCC subunit) overexpression we could prevent depressed myocyte contractility after MI and use it to test the idea that preventing depression of myocyte Ca2+ handling defects could avert post MI cardiac pump dysfunction. In the other model, mice with Ser2808 in RyR2 replaced by alanine (S2808A) to prevent the phosphorylation at this site were used to determine whether loss of functional PKA phosphorylation site at Ser2808 could protect against cardiac dysfunction progression after MI. beta2a myocytes had increased Ca2+ current; contraction and Ca2+ transients (versus controls) and beta2a hearts had increased performance before MI. After MI, ventricular dilation, myocyte hypertrophy, and depressed cardiac pump function was greater in beta2a versus control hearts. There was also an increased rate of myocyte death in beta2a hearts after MI and survival was significantly reduced in these animals. We concluded that maintaining myocyte contractility after MI, by increasing Ca2+ influx, depresses rather than improves cardiac pump function. Baseline cardiac function was similar in wild type (WT) and RyR-S2808A mice before MI. After MI, there was no significant difference between WT and RyR-S2808A mice in EF and FS at 4 weeks. ICa-L € in WT and RyR-S2808A myocytes was not significantly different. There were significant ISO responses in all myocytes, and no appreciable differences in responsiveness were found. Contractions and Ca2+ transients were not significantly different in WT and RyR-S2808A myocytes after MI. In conclusion, preventing PKA phosphorylation of RyR at Ser2808 after MI does not protect the heart or its myocytes. The role of RyR phosphorylation at other sites on abnormal Ca2+ handling in diseased hearts is yet to be defined.
Temple University--Theses

Heart failure is a common condition which carries a high mortality and morbidity. Despite improved medical therapy the outcomes for heart failure with a reduced ejection fraction remain poor. Cardiac resynchronisation therapy has revolutioned the treatment of patients with heart failure with a reduced ejection fraction and dyssynchrony, refactory to medical therapy, improving morbidity and mortality. Unfortunately a significant minority fail to respond to this expensive therapy, which is challenging for both the patient and society. Over the last 15 years research has focused on attempting to predict non-response. Evidence suggests wider QRS duration and bundle branch morphology on the resting electrocardiograph are the most important predictors of response and outcome following implantation of a cardiac resynchronisation device. However, the non-response rate remains unchanged despite extensive research. Molecular systems have been shown to alter with the development and progression of heart failure. Many of these systems are now utilised in the diagnosis and prognostication of heart failure. Cardiac resynchronisation therapy device implantation has been shown to alter these dysregulated molecular systems. Specific circulating biomarkers reflect these respective systems. Cardiac extracellular matrix is a dynamic support structure that has altered turnover in heart failure and is affected when cardiac resynchronisation devices are implanted. Micro ribonucleic acids have been observed recently to be important in molecular systems regulation and dysregulation has been observed in heart failure. Furthermore altered expression following cardiac resynchronisation therapy device implantation has been reported. The evidence suggests circulating biomarkers for these systems have the potential to predict response. Our prospective study examined specific biomarkers that the literature suggests has the potential to predict response, but the evidence is currently inconclusive. Moreover we utilised other important patient variables known to be predictors from the wider literature and our own retrospective cohort analysis of response to test alongside specific circulating biomarkers. We offer an informed pilot study to test important circulating biomarkers for their clinical ultility to predict heart failure patient’s ability to respond to cardiac resynchronisation therapy.

The aim was to investigate associations of fitness and types and levels of physical activity with subsequent risk of cardiovascular disease. Four large-scale longitudinal cohort studies were used. The exposures were different measures related to physical activity and the outcomes were obtained through linkage to the Swedish In-Patient Register. In a cohort of 466 elderly men without pre-existing cardiovascular disease, we found that skeletal muscle morphology was associated with risk of cardiovascular events. A high amount of type I (slow-twitch, oxidative) skeletal muscle fibres was associated with lower risk of cardiovascular events and high amount of type IIx was associated with higher risk of cardiovascular events. This association was only seen among physically active men. Among 39,805 participants in a fundraising event, higher levels of both total and leisure time physical activity were associated with lower risk of heart failure. The associations were strongest for leisure time physical activity. In a cohort of 53,755 participants in the 90 km skiing event Vasaloppet, a higher number of completed races was associated with higher risk of atrial fibrillation and a higher risk of bradyarrhythmias. Further, better relative performance was associated with a higher risk of bradyarrhythmias. Among 1,26 million Swedish 18-year-old men, exercise capacity and muscle strength were independently associated with lower risk of vascular disease. The associations were seen across a range of major vascular disease events (ischemic heart disease, heart failure, stroke and cardiovascular death). Further, high exercise capacity was associated with higher risk of atrial fibrillation and a U-shaped association with bradyarrhythmias was found. Higher muscle strength was associated with lower risk of bradyarrhythmias and lower risk of ventricular arrhythmias. These findings suggest a higher rate of atrial fibrillation with higher levels of physical activity. The higher risk of atrial fibrillation does not appear to lead to a higher risk of stroke. In contrast, we found a strong inverse association of higher exercise capacity and muscle strength with vascular disease. Further, high exercise capacity and muscle strength are related to lower risk of cardiovascular death, including arrhythmia deaths. From a population perspective, the total impact of physical activity on cardiovascular disease is positive.

The overall aim of this thesis was to describe the prevalence of depressive symptoms, sleep disordered breathing (SDB) and sleep complaints, as well as to investigate the prognostic value of health-related quality of life (Hr-QoL) and depressive symptoms on mortality in an elderly community living population with a focus on those with impaired systolic function/heart failure (HF). Descriptive, prognostic and explorative study designs were used to examine if a single question about global perceived health (GPH) is associated with the domains of Hr-QoL as assessed by the SF-36 (I), as well as to evaluate whether GPH provided prognostic information concerning cardiovascular mortality (II). The aim was also to evaluate if depressive symptoms are associated with mortality (III), and to describe the prevalence of SDB and its relationship to impaired systolic function, different insomnia symptoms, as well as excessive daytime sleepiness (IV). In primary care elderly patients with HF, GPH correlated to the physical and mental aspects of Hr-QoL. Patients who rated poor GPH also scored worse physical and mental Hr-QoL compared to patients with good GPH, but the mental aspect of Hr-QoL was however not significant (p<0.07) (I). Moreover, GPH also had an independent association with cardiovascular mortality during a ten-year follow-up. Compared to patients with good GPH, those who scored poor GPH had a four times increased risk for cardiovascular mortality (II). A total of 24% of the patients with HF suffered from depressive symptoms, not significantly different compared to 19% among those without HF. Depressive symptoms were a poor prognostic sign during the six-year follow-up and HF patients with depressive symptoms had the highest risk for cardiovascular mortality compared to HF patients without depressive symptoms (III). SDB is common among elderly people living in the community, almost one quarter (23%) had moderate or severe SDB. However, people with moderate impaired systolic function had a median apnea hypopnea index that was more than twice as high compared to those with normal systolic function (10.9 vs. 5.0, p<0.001). No obvious associations between SDB and excessive daytime sleepiness or the insomnia symptoms; difficulties maintaining sleep; non-restorative sleep; or early morning awakenings were detected. Difficulties initiating sleep were however more common in those with moderate or severe SDB (IV). GPH can be used as a simple tool in clinical routine practice as an aid in identifying patients in need of additional management. SDB is a common phenomenon among elderly people and associated with impaired systolic function, but with a limited impact on subjective sleep complaints. Depressive symptoms were shown to be a poor prognostic sign and may amplify the patient’s experience of suffering. Screening for depressive symptoms could therefore be an important action in the management of patients with HF.

In cardiovascular disease the definition and the detection of the ECG parameters related to repolarization dynamics in post MI patients is still a crucial unmet need. In addition, the use of a 3D sensor in the implantable medical devices would be a crucial mean in the assessment or prediction of Heart Failure status, but the inclusion of such feature is limited by hardware and firmware constraints. The aim of this thesis is the definition of a reliable surrogate of the 500 Hz ECG signal to reach the aforementioned objective. To evaluate the worsening of reliability due to sampling frequency reduction on delineation performance, the signals have been consecutively down sampled by a factor 2, 4, 8 thus obtaining the ECG signals sampled at 250, 125 and 62.5 Hz, respectively. The final goal is the feasibility assessment of the detection of the fiducial points in order to translate those parameters into meaningful clinical parameter for Heart Failure prediction, such as T waves intervals heterogeneity and variability of areas under T waves. An experimental setting for data collection on healthy volunteers has been set up at the Bakken Research Center in Maastricht. A 16 – channel ambulatory system, provided by TMSI, has recorded the standard 12 – Leads ECG, two 3D accelerometers and a respiration sensor. The collection platform has been set up by the TMSI property software Polybench, the data analysis of such signals has been performed with Matlab. The main results of this study show that the 125 Hz sampling rate has demonstrated to be a good candidate for a reliable detection of fiducial points. T wave intervals proved to be consistently stable, even at 62.5 Hz. Further studies would be needed to provide a better comparison between sampling at 250 Hz and 125 Hz for areas under the T waves.

L’insuffisance cardiaque est un problème de santé publique dans les pays développés, touchant 1 à 2% de la population générale, mais dont la prévalence atteint 10% après 70 ans. Les progrès thérapeutiques ont permis d’améliorer le pronostic des patients, notamment ceux ayant une altération de la fonction systolique ventriculaire gauche. Les troubles du rythme sont fréquents et nécessitent une pris en charge particulière au cours des situations d’insuffisance cardiaque. Cependant, il reste des questions non résolues : comment améliorer l’efficacité du traitement de l’insuffisance cardiaque à fonction systolique préservée, comment mieux sélectionner les patients pouvant bénéficier de la prévention primaire de la mort subite par un défibrillateur implantable, les patients âgés peuvent-ils bénéficier de la même prise en charge que les patients plus jeunes, et pour finir comment améliorer les résultats de l’ablation de fibrillation auriculaire dans les situations d’insuffisance cardiaque. Nous avons mis en place une étude prospective chez des patients présentant une dysfonction diastolique pour évaluer l’intérêt de l’algorithme de surveillance de l’apnée du sommeil disponible dans des stimulateurs cardiaques. En parallèle, nous avons analysé l’impact de l’évaluation par résonance magnétique des patients candidats à un défibrillateur sur la prédiction des évènements rythmiques, mais aussi le devenir des patients de plus de 75 ans appareillés avec un système de resynchronisation cardiaque. Enfin, nous nous sommes intéressés aux résultats d’un nouveau système de cartographie électroanatomique ultra-haute densité pour guider les procédures d’ablation de troubles du rythme supraventriculaires complexes chez des patients insuffisants cardiaques comparés à des patients contrôles
Heart failure is a major public health issue in developed countries, with a prevalence of 1-2% of global population, rising to 10% after 70 years of age. Therapeutic progresses have succeeded in improving patients’ prognosis, particularly in case of reduced left ventricular ejection fraction. Rhythm abnormalities are frequent, and need special consideration in case of heart failure. Meanwhile, there are still some gaps in the evidence: heart failure with preserved systolic function is complex and difficult to treat, primary prevention of sudden cardiac death is effective but there is a need to better select candidates, whether elderly patients should be treated as younger individuals, and finally how to improve outcomes of atrial fibrillation catheter ablation. Firstly, we have conducted a prospective study to evaluate the Sleep Apnea Monitoring algorithm provided in a novel pacemaker in patients with diastolic dysfunction. Besides, we analyzed whether magnetic resonance imaging could predict cardiac outcomes in patients with an implantable cardioverter defibrillator better than echocardiography. We also reported the outcomes of the cardiac resynchronization therapy in patients ≥75 years old compared to younger patients. Finally, we studied the results of a novel ultra-high density mapping system to guide ablation procedures of complex atrial arrhythmias in heart failure patients compared to controls

L’assistance ventriculaire constitue une voie thérapeutique prometteuse de l’insuffisance cardiaque terminale. En dépit des progrès, notamment dans le développement des assistances de type shunt ventriculo-aortique, les écueils relatifs à l’encombrement, à l’alimentation et/ou aux interactions avec le sang de ces dispositifs limitent leur application clinique. Récemment, le concept de Compression Cardiaque Directe (DCC) apparaît comme une piste prometteuse en palliant les difficultés sus-citées. Dans ce travail de thèse, nous avons mis l’accent sur la conception et le test de faisabilité d’une solution de Compression Cardiaque Directe de type mécanique et entièrement implantable appelée l’Exosquelette Cardiaque. Notre travail expérimental a porté, dans un premier temps, sur la conception assistée par ordinateur et sur la modélisation numérique permettant ainsi d’optimiser et de prédire (i) les interactions tissus myocardiques/dispositifs et (ii) les pressions ventriculaires générées. Ensuite, un prototype fonctionnel a été réalisé par fabrication additive (titane, polymères) en s’appuyant sur les données issues de la modélisation et en respectant les contraintes énergétiques, mécaniques et architecturales anatomiques. Enfin, nous avons conduit une phase d’évaluation du potentiel de ce dispositif original sur un modèle de cœur ex vivo. Nous avons pu concevoir et valider un modèle numérique fondé sur le principe des éléments finis. Ce modèle à la fois simple et robuste, a permis de simuler (i) l’impact des points de fixation du dispositif sur le tissu cardiaque, (ii) l’efficacité de la compression externe sur la genèse des pressions intraventriculaires et (iii) l’influence de la compression mécanique externe sur le tissu cardiaque. Le prototype issu de ce travail de thèse a pu produire des résultats prometteurs concernant (i) la restauration physiologique de la pression intraventriculaire, (ii) la consommation énergétique suffisamment basse et (iii) le design compatible avec les contraintes anatomiques thoracique. L’ensemble de ces résultats esquissent la possibilité d’une implantation totale de l’Exosquelette Cardiaque chez le patient
Ventricular assistance is a promising therapeutic pathway for terminal chronic heart failure. Notwithstanding the progress made for the development of aorto-ventricular shunt pump among other things, the difficulties relatives to footprint, power supply and/or blood-device interactions are somehow limiting their clinical applications. Recently, direct cardiac compression (DCC) was suggested as a promising lead to overcome the difficulties mentioned above. In this work, we focused on the design and the feasibility of an implantable and mechanical Direct Cardiac Compression device called: The Cardiac Exosqueleton. Our experimental work used Computer Assisted Design (CAD) and numerical modeling to optimize and predict (i) tissue-device interactions and (ii) pressure generation inside ventricular cavities. Then, a functional prototype was realized by additive manufacturing (titanium, polymer) with the help of modeling data and with respect to the anatomical, mechanical and energetical limitations. Finally, we conducted an evaluation of the ability of our device on both in vitro setup and ex vivo heart. We were able to conceive and validate a numerical model based on finite element techniques. This simple yet robust model allowed us to study (i) the impact of suture fixation of a device at the apex of the heart, (ii) the influence of the direct cardiac compression on intracardiac pressures and (iii) overall and local tissue stress in the myocardium. Our prototype showed promising results concerning (i) the restoration of physiological intraventricular pressures, (ii) a low energy consumption and (iii) a shape that is compatible with the thoracic anatomical constraints. All of these results allow us to envision a total implantation of the cardiac exoskeleton into the patient

Increases in internal dimensions of the chambers of the heart (cardiac dilatation), mediated by right shifts in cardiac chamber diastolic pressure-volume (P-V) relations, predict mortality in patients with established heart failure. However, the mechanisms responsible for the transition from concentric cardiac hypertrophy to cardiac dilatation are unclear. Recent evidence suggests that decreases in the cross-linked properties of myocardial collagen may increase the propensity of collagen to cleavage and hence reduce cardiac myocyte tethering, thus promoting cardiac dilatation. However, decreases in myocardial collagen cross-linking may also reduce myocardial stiffness, thus explaining right shifts in cardiac diastolic P-V relations. In the present dissertation I evaluated whether right shifts in diastolic P-V relations produced by chronic β-adrenoreceptor activation (isoproterenol, a β-adrenoreceptor agonist, 0.02 mg.kg-1.day) in spontaneously hypertensive rats (SHR) with compensated cardiac hypertrophy (12 months of age), can be explained by adverse chamber remodelling or alterations in the myocardial material properties of the heart. After 7 months of daily isoproterenol administration, SHR had marked right shifts in left ventricular (LV) diastolic P-V relations as determined in isolated, perfused hearts, with increases in the volume intercept of these relations, a change that translated into increases in LV cavity diameters (echocardiography). LV dilatation was associated with reductions in LV pump function (decreases in LV endocardial fractional shortening and the slope of the LV systolic P-V relation [LV E]). The reductions in pump function were attributed to the LV dilatation rather than to alterations in intrinsic myocardial contractile properties as LV midwall fractional shortening and myocardial systolic elastance (LV En) were unchanged. Although SHR not receiving isoproterenol had increases in the LV diastolic wall thickness-to-radius ratio, a change commensurate with compensatory concentric LV hypertrophy, LV wall thickness-to-radius ratio in SHR exposed to chronic β-adrenoreceptor activation was reduced to values similar to those noted in normotensive Wistar Kyoto (WKY) control rats, despite further increases in LV weight. SHR not receiving isoproterenol had a marked increase in myocardial stiffness (slope of the linearized LV diastolic stress-strain relationship) as compared to WKY rats, a change that was associated with an increased myocardial collagen of the cross-linked phenotype. Although SHR receiving daily isoproterenol had further increases in myocardial collagen, this did not translate into changes in LV diastolic myocardial stiffness, as the further increase in myocardial collagen was of the non cross-linked phenotype. However, through a susceptibility to digestion, this collagen phenotype could have contributed to LV dilatation. In conclusion, these data suggest that LV dilatation in SHR following chronic β-adrenoreceptor activation is attributed to adverse chamber remodelling rather than to alterations in myocardial material properties as indexed by diastolic stress-strain relations.

碩士
弘光科技大學
健康事業管理研究所
105
Background Heart failure is one of the ten causes of death in Taiwan,provide the nice rehabilitation program for heart disease, can improve the patient's exercise tolerance, and promote the organization for the utilization of oxygen, making life quality improvement. Therefore, this study for the heart failure patients with 12-weeks rehabilitation exercise program to explore this customized rehabilitation exercise program, to improve the heart failure patients with motor tolerance, functional activity of daylife and discussion the effect of the program. Purpose To explore the benefits of heart involvement, heart-related functional data, quality of life, and 6-minute walking distance in patients with chronic heart failure. Methods The results were as follows: NYHA Ⅰ ~ Ⅲ, EF <50% excluded from the case of rehabilitation can not be performed, and the random distribution was divided into control group (n = 21) and the experimental group (n = 19). The control group to maintain the general clinical care, the experimental group according to exercise test results, the design of individual sports training, with the case management approach, every two weeks to assess the status of patients. The patient's quality of life scale, the 6-minute walk test, the cardiac output and the maximum oxygen uptake test for the cardiopulmonary exercise were recorded during the period of receipt. Two groups of data were taken to repeat the measurement to compare the effectiveness of the intervention. Results The results showed that the lung function (83.5% vs.88.7%, P = 0.01), the maximum oxygen uptake (18.3 vs.21.0 ml / kg / min, P <0.01) and the quality of life scores were measured by Wilicoxon signed rank test (404 vs.436, P = 0.01). The experimental group showed a significant improvement and a statistically significant effect compared with the control group (38.12 vs.19.6, P <0.01) (14.7% vs -7.1%), quality of life (48.4% vs 0.8%) and MET (-21% VS-12.4%) were measured by independent sample t test. The exercise tolerance and quality of life Compared with the control group, the experimental group was significantly improved and statistically significant. Conclusions The study provided heart failure patients with cardiac rehabilitation program, can enhance the maximum oxygen uptake of 14.7%, 6 minutes walking distance increased by 32 meters, life quality score increased by 48.5%.

RESUMO: Introdução A insuficiência cardíaca crónica é conhecida como síndrome complexa, associada a elevada mortalidade e incapacidade, envolvendo múltiplos mecanismos fisiopatológicos, neuro-hormonais, endoteliais e inflamatórios. Além da terapêutica médica optimizada, a terapêutica não farmacológica, como a ressincronização cardíaca e o treino de exercício, assume um papel fundamental. Na insuficiência cardíaca avançada, doentes com critérios para terapêutica de ressincronização cardíaca (CRT) têm sido exaustivamente estudados, apesar da maioria dos estudos não se ter dedicado à diversidade de efeitos e mecanismos fisiopatológicos envolvidos, nos doentes mais gravemente sintomáticos. Nesta população com insuficiência cardíaca avançada tratada com CRT, estudos relativos aos efeitos e mecanismos do treino de exercício, especificamente exercício intervalado de alta intensidade, são ainda poucos e de pequena dimensão. Hipótese Hpótese principal formulada: Existe benefício em associar um programa de treino de exercício de alta intensidade, de longa duração, após ressincronização cardíaca em doentes com insuficiência cardíaca avançada. Hipótese secundária: 2 Estão envolvidos vários mecanismos fisiopatológicos, contribuindo diferentemente para o benefício do treino de exercício após CRT e para o benefício de CRT sem programa de exercício subsequente, em doentes com insuficiência cardíaca avançada. Objectivos O objectivo primário desta tese foi determinar os efeitos do programa de exercício intervalado de alta intensidade (HIIT), de longa duração, sobre a classe funcional clínica, qualidade de vida, capacidade funcional de exercício, função cardíaca e remodelagem ventricular, em doentes com insuficiência cardíaca avançada após implante do ressincronizador. O objectivo secundário pretendeu avaliar o papel potencial de diferentes mecanismos fisiopatológicos nos benefícios do treino de exercício após CRT, HIIT, e após CRT sem exercício subsequente: função endotelial, função do sistema nervoso autónomo, processo inflamatório e apoptose. Metodologia Efectuámos um ensaio controlado aleatorizado para determinar os efeitos da intervenção de exercício, HIIT, em doentes com insuficiência cardíaca avançada após CRT. Os critérios de inclusão foram, doentes com insuficiência cardíaca estável, em classe III-IV (NYHA), sob terapêutica farmacológica optimizada, referenciados para CRT pelas recomendações actuais presentes, etiologia isquémica e não isquémica, com idade superior a 18 anos. Os critérios de exclusão incluiram insuficiência cardíaca instável, doença ortopédica ou muscular incapacitante para exercício e residência geograficamente distante do hospital. Os doentes que preencheram os critérios de inclusão foram aleatorizados para treino de exercício intervalado de alta intensidade ou para grupo controlo (EXTG e CG, respectivamente). 3 A aleatorização, realizada por um investigador independente, foi estratificada, baseada na idade (<65 ou >65 anos), sexo, etiologia (isquémica e não isquémica) e gravidade de disfunção ventricular esquerda (fracção de ejecção ventricular esquerda <20 ou >20%). Os doentes com os mesmos critérios de inclusão, que não aceitaram a intervenção exercício ou que viviam longe, sem os restantes critérios de exclusão, foram adicionalmente estudados como cohort prospectivo para avaliação dos efeitos e mecanismos da intervenção CRT. Durante o periodo de Janeiro 2012 a Março 2015, todos os doentes com insuficiência cardíaca e critérios para ressincronização cardíaca elegíveis foram estudados. O programa de treino de exercício foi iniciado 1 mês após implante de cardioressincronizador e durou 6 meses com frequência bissemanal, consistindo em sessões de 60 minutos, realizadas no hospital, monitorizadas e supervisionadas. Incluiu treino aeróbio intervalado de alta intensidade (HIIT), adaptado a partir do protocolo de Wisloff, e exercícios de resistência, flexibilidade e coordenação. Os momentos do estudo usados para avaliação das variáveis independentes foram: momento basal, pré implante do ressincronizador (M1), aos 3 meses após exercício, correspondendo a 4 meses após implante (M2) e aos 6 meses após exercício, correspondendo a 7 meses após implante (M3). As variáveis dependentes estudadas foram: classe functional clínica (NYHA), scores de qualidade de vida (questionário HeartQol), parâmetros de função cardíaca e remodelagem reversa (determinadas por ecocardiografia e doseamento plasmático de péptido natriurético, BNP), de capacidade funcional de exercício (determinadas por prova de esforço cardio-respiratória, CPT), de função do sistema nervoso autonómico, SNA (por cintigrafia cardíaca com 123I-MIBG, prova de esforço cardio-respiratória e análise da variabilidade da frequência cardíaca no Holter-24 horas), de função endotelial e rigidez arterial (determinada por doseamento de NO, óxido nítrico, e por PAT, tonometria arterial periférica), marcadores de inflamação e apoptose (medição de proteína C reactiva de alta sensibilidade, hs-CPR, factor de necrose tumoral alfa, TNF-α, interleucina-6, IL-6, fracção solúvel do cluster de diferenciação 40, sCD40, fracção solúvel do ligando Fas, sFasL) e frequência de eventos major cardiovasculares aos 6 meses de exercício. 4 As excepções aos 3 momentos de avaliação foram: 123I-MIBG cintigrafia cardíaca, realizada antes do CRT (M1) e aos 6 meses de exercício (M3), análise de variabilidade da frequência cardíaca por estudo Holter-24horas, realizado apenas basal, pre-CRT (M1) e frequência de eventos, avaliada em M3. A segurança do treino de exercício HIIT foi avaliada. A resposta ecocardiográfica foi definida pelo aumento de pelo menos 5% da fracção de ejecção ventricular esquerda (LVEF), em valor absoluto e a resposta clínica como melhoria de pelo menos 1 classe funcional clínica (NYHA). A resposta funcional foi definida como o aumento de pelo menos 1 ml/kg/min de VO2p. Resultados A partir de um cohort inicial de 121 doentes com insuficiência cardíaca selecionados para CRT, foram aleatorizados 62 doentes. Realizaram programa de treino de exercício HIIT, 22 doentes (EXTG), idade média 67,5±9,8%, 22,7% do sexo feminino, 40% isquémicos, LVEF basal 26,68±6,21%, enquanto 28 doentes foram incluídos no grupo controlo (CG). As características demográficas e clínicas basais foram idênticas estatisticamente. No grupo aleatorizado (n=50), todos os doentes tiveram benefício significativo, aos 6 meses após início do exercício, relativamente a: diminuição da classe clínica de NYHA (p <0,001), melhoria do score de qualidade de vida HeartQol (p <0,001), aumento da LVEF, fracção de ejecção ventricular esquerda (p <0,005), diminuição dos volumes ventriculares esquerdos, LVED, tele-diastólico (p < 0,05) e LVES, tele-sistólico (p <0,02). Verificou-se uma diferença significativa da classe funcional clínica (NYHA), nos dois grupos aleatorizados, com maior diminuição no EXTG (p=0,034). Apenas no EXTG, se encontrou um aumento significativo da duração da prova de esforço cardio-respiratória, aos 3 meses (p=0,017) e aos 6 meses (p=0,008). O tempo para o limiar anaeróbio, VAT, aumentou significativamente no EXTG aos 3 meses (p= 0,006) e aos 6 meses (p=0,004), sendo significativamente diferente do CG aos 3 meses (p=0,006) e apresentando uma tendência para significado estatístico aos 6 meses (p=0,064), momento em que a variação foi também significativa no CG. O TNF-α diminuiu significativamente apenas no EXTG, aos 6 meses (p=0,016), com uma diferença estatística significativa em relação ao 5 CG (p=0,008). Não se verificaram diferenças significativas nas variações dos parâmetros ecocardiográficos entre os dois grupos aleatorizados. Relativamente ao número de respondedores, no grupo de treino de exercício foram identificados mais respondedores clínicos (95%) e ecocardiográficos (81,8%) que no grupo controlo (78,5% e 72,7%, respectivamente), após 6 meses de exercício. A diferença no número de respondedores entre os 2 grupos aleatorizados, não atingiu contudo significado estatístico (provavelmente pela dimensão da amostra), mas com uma tendência para mais respondedores clínicos no grupo de exercício. A diferença no numero de respondedores funcionais, apesar de em numero tendencialmente superior no grupo de exercício (77,2%) não foi significativa. O programa HIIT mostrou ser seguro, sem eventos major ou minor durante o exercício. Aos 6 meses de exercício (7 meses após implantação do ressincronizador), registaram-se 9% de eventos no grupo exercício e 10,7% no grupo controlo. Verificou-se ocorrência de morte ou internamento hospitalar em 1/22 doentes (4,5%) do grupo de exercício e em 3/28 doentes (10,7%) do grupo controlo. A única morte nos doentes aleatorizados ocorreu no grupo controlo, 1/28 doentes (3,5%). No total do cohort de doentes com CRT verificou-se um benefício significativo após 7 meses de implantação: redução da classe funcional NYHA (p <0,001), aumento do score HeartQol (p <0,001), aumento da LVEF (p < 0,001), diminuição do volume tele-sistólico ventricular esquerdo (p=0,001), aumento do valor absoluto de GLS, strain global longitudinal, (p=0,003), relação E/e’, rácio entre onda E do fluxo de câmara de entrada do ventrículo esquerdo e e’ médio de doppler tecidular do anel mitral, (p=0,009), redução da massa ventricular esquerda (p=0,026), redução do VE/VCO2 slope, declive da razão entre ventilação minuto e produção de CO2, (p=0,003), aumento da duração do teste cardiopulmonar (p=0,002), aumento do tempo para VAT, limiar anaeróbio (p=0,001), redução do HRR1 (frequência cardíaca de recuperação ao primeiro minuto), (p=0,015), redução do HRR6 (frequência cardíaca de recuperação ao 6º minuto), (p=0,033) e aumento do VO2p, consumo de oxigénio pico, (p=0,04). Na amostra total dos doentes insuficientes cardíacos com CRT (incluindo 18% dos doentes submetidos a exercício) 75,6% foram respondedores clínicos, 63,9% respondedores ecocardiográficos e 62,8% respondedores funcionais. Os respondedores ecocardiográficos ao CRT tinham diferenças significativas nos parâmetros de base e na variação de alguns parâmetros: M1, menores volumes ventriculares esquerdos, maior TAPSE, maior SDNN (standard 6 deviation NN interval), maior heart-mediastinum ratio precoce (HMRe) e tardio (HMRl); M3-M1, maior aumento de LVEF, maior redução de volume LVES, maior aumento do valor absoluto de GLS e tendência para maior aumento de VO2p. Os respondedores tiveram menor número de eventos major registados em M3. Analizando todos os doentes com CRT, valores de 123MIBG HMRl>1,5 identificaram mais respondedores ecocardiográficos (probabilidade 2 vezes superior), apenas em não isquemicos. Os eventos aos 7 meses após CRT, M3, morte ou admissão hospitalar ou arritmia ocorreram em 14,8% da população total e em 16,1% dos doentes não submetidos a exercício.A morte ocorreu em 4,9% no grupo total e em 6% do grupo não submetido a exercício. Conclusão No presente ensaio aleatorizado e controlado, realizado numa amostra de doentes com insuficiência cardíaca avançada, referenciada para CRT, o exercício HIIT após implante do ressincronizador provou ser benéfico e seguro, associado a um maior número de respondedores ecocardiográficos e clínicos, acompanhado de uma melhoria clínica mais significativa, evidenciando o benefício adicional ao CRT. A melhoria do componente periférico da insuficiência cardíaca condicionada pelo exercício foi demonstrada pelo aumento significativo da capacidade funcional ao esforço e do tempo para VAT, acompanhada de maior número de respondedores funcionais, tendo-se verificado um efeito modulatório sobre a inflamação que poderá ter contribuído para este efeito. Não foram demonstrados benefícios do exercício na função endotelial, no sistema nervoso autonómico e na apoptose. Ocorreram menos eventos major aos 6 meses em doentes submetidos a HIIT. A avaliação adicional dos doentes com CRT no estudo observacional demonstrou melhoria clínica, de qualidade de vida e de função ventricular sistólica e diastólica significativa, mesmo excluindo aqueles que fizeram treino de exercício. O efeito central do CRT na remodelagem cardíaca demonstrou ser crucial, com melhoria das diversas variáveis ecocardiográficas. Contrariamente, não se demonstraram efeitos periféricos benéficos do CRT, VO2p, duração CPT ou tempo VAT, aos 7 meses, uma vez excluídos os 7 doentes que fizeram programa de exercício. O sistema nervoso autónomo demonstrou ser um mecanismo relevante na resposta ao CRT, mas apenas em insuficientes cardíacos não isquémicos. Não foram demonstrados efeitos benéficos do CRT na função endotelial, inflamação ou apoptose. Registaram-se mais eventos em doentes sem terapêutica de exercício. Dos resultados desta tese, que verificam as hipóteses colocadas, podemos salientar que em doentes com insuficiência cardíaca avançada a intervenção de treino de exercício intervalado de alta intensidade, supervisionado, , após implantação de ressincronizador cardíaco é uma terapêutica não farmacológica segura e tem benefício adicional demonstrado relativo à CRT, resultando em menor número de doentes não respondedores. Esta intervenção não teve efeito deletério sobre a remodelagem reversa e alguns resultados apontam para potencial benefício. Os mecanismos envolvidos estão ligados particularmente ao componente periférico da insuficiência cardíaca, resultando em diminuição da gravidade dos sintomas clínicos, melhoria da capacidade funcional e modulação positiva da resposta fisiopatológica inflamatória.
ABSTRACT: Introduction Chronic heart failure is known to be a complex syndrome, associated to high mortality and disability, involving multiple pathophysiologic mechanisms, neuro-hormonal, endothelial and inflammatory. Besides optimized medication, the nonpharmacologic therapy, like cardiac resynchronization and exercise training, plays a fundamental role. In advanced heart failure, patients with criteria for cardiac resynchronization therapy (CRT) have been studied extensively, though most of the studies were not dedicated to the diversity of effects and involved pathophysiologic mechanisms, in most severely symptomatic patients. In this advanced heart failure population treated with CRT, studies regarding exercise training effects and mechanisms, specifically high intensity interval exercise, are still few and small-sized. 8 Hypothesis Main hypothesis formulated: It is beneficial to associate a high intensity interval training exercise program, long duration, after cardiac resynchronization in advanced Heart Failure Patients. Secondary hypothesis: Several pathophysiologic mechanisms are involved, contributing differently to the exercise training benefit after CRT and to the benefit of CRT without subsequent exercise program in advanced HF patients. Aims The primary aim of this thesis was to determine the effects of a long-term High Intensity Interval Exercise Training (HIIT) program on clinical functional class, quality of life, exercise functional capacity, cardiac function and remodeling, in advanced heart failure patients after cardiac resynchronizer implant. Secondary aim intends to evaluate the potential role of different pathophysiologic mechanisms in the benefits of exercise training after CRT, HIIT, and of CRT without subsequent exercise: endothelial function, autonomic nervous system function, inflammatory process and apoptosis. Methodology A randomized controlled trial was performed to determine the effects of exercise intervention, HIIT, in advanced heart failure patients after CRT. The inclusion criteria considered patients with stable heart failure, class III-IV (NYHA), receiving optimal pharmacologic therapy, assigned to CRT by present guidelines, ischemic and non ischemic etiology, older than 18 years. Exclusion criteria included unstable HF patients, exercise incapacitating orthopedic or muscular disease and geographically long distance living. 9 Patients who fulfilled the inclusion criteria were randomized for long duration high intensity interval exercise training or for control group (EXTG and CG, respectively). Randomization, performed by an independent investigator, was stratified, based on age (1.5 identified more CRT echocardiographic responders (2-fold probability), only in nonischemic. Events at 7 months after CRT, M3, cardiac death or hospital admission or arrhythmia occurred in 14.8% of total population and in 16.2% of nonrandomized patients. Death occurred in 4.9% in total group and in 6% in nonrandomized group. Conclusion In this controlled randomized trial, performed in a sample of advanced HF patients referred to CRT, HIIT exercise after cardiac resynchronizer implant proved to be beneficial and safe, associated to an increased number of clinical and echocardiographic responders and with more significant clinical improvement, suggesting an additional benefit to CRT. The improvement of the peripheral component of heart failure caused by exercise was demonstrated by CPT duration and time to VAT significant increase, associated with more functional responders, along with positive modulation of inflammation, which might have contributed to this effect. No significant effects were demonstrated in endothelial or autonomic nervous system function. Less major events occurred in the HIIT group after the 6 months of training. The additional evaluation of CRT patients in the observational study of the total HF sample, showed a beneficial effect on symptoms severity, quality of life and systolic and diastolic LV function, even excluding those who performed exercise. Central effect of CRT on cardiac remodeling demonstrated to be crucial, with echocardiographic improvement of several variables. Once EXTG patients were excluded, the restant CRT patients did not show significant improvement at 7 months of VO2p, CPT duration or time to VAT, meaning CRT had no effect on HF peripheral component. Autonomic nervous system demonstrated to be a relevant mechanism for CRT response, but only in nonischemic HF. No beneficial effects of CRT were noticed in endothelial function, inflammation or apoptosis. More events were registered in patients who did not exercise. From these thesis results, we may accept, in advanced heart failure patients, exercise (HIIT) as safe and beneficial nonpharmacologic therapy with demonstrated additional benefit, regarding CRT, resulting in fewer patients with CRT nonresponse. This 13 intervention had no deleterious effect on reverse remodeling and some results point out to a potential benefit. The involved mechanism especially regards the peripheral component of HF, manifested by the decrease in clinical symptoms severity, improvement in functional capacity and positive modulation of pathophysiologic inflammatory response.
FCT PTDC/DES/120249/2010

no
Dear Editor In undertaking studies of palliative care in heart failure and chronic obstructive pulmonary disease (COPD) in the UK, we identified procedural, conceptual and ethical challenges that may arise from one feature of The End of Life Care Strategy for England.1 The strategy presents the question, ‘Would I be surprised if the person in front of me was to die in the next six months or one year?’ as a prompt to initiate discussion of endof-life care needs and preferences (paragraph 3.23). We believe this question is inappropriate in heart failure and COPD and its use will inhibit the initiation of a palliative care approach with these patients.