Background and objective: Major risk factors for congestive heart failure (CHF) are myocardial infarction, hypertension, diabetes, atrial fibrillation, smoking, left ventricular hypertrophy (LVH) and obesity. However, since these risk factors only explain part of the risk of CHF, we investigated whether persistent organic pollutants (POPs) might also play a role. Methods: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, left ventricular ejection fraction, (EF), E/A-ratio and isovolumic relaxation time (IVRT), were determined by echocardiography and serum samples of 21 POPs were analyzed in serum measured by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS) in 998 subjects all aged 70 years. Results: In this cross-sectional analysis, high levels of several of the polychlorinated biphenyls (PCB congeners 99, 118, 105, 138, 153, and 180) and octachlorodibenzo-p-dioxin (OCDD) were significantly related to a decreased EF. Some POPs were also related to a decreased E/A-ratio (PCBs 206 and 209). All the results were adjusted for gender, hypertension, diabetes, smoking, LVH and BMI, and subjects with myocardial infarction or atrial fibrillation were excluded from the analysis. Conclusions: Circulating levels of POPs were related to impairments in both left ventricular systolic and diastolic function independently of major congestive heart failure risk factors, suggesting a possible role of POPs in heart failure.

Diagnosis of diabetes mellitus, presence of hyperglycemia, and/or insulin resistance confer cardiovascular risk, particularly for diastolic dysfunction. Diabetes is associated with elevated myocardial norepinephrine (NE) content, enhanced sympathetic nervous system (SNS) activity, altered resting heart rate, and depressed heart rate variability. Positron emission tomography (PET) using the NE analogue [11C]meta-hydroxyephedrine ([11C]HED) provides an index of myocardial sympathetic neuronal integrity at the NE reuptake transporter (NET). The hypothesis of this project is that (i) hyperglycemia imparts heightened sympathetic tone and NE release, leading to abnormal sympathetic neuronal function in the hearts of diabetic rats, and (ii) these abnormalities may be reversed or prevented by treatments to normalize glycemia. Sprague Dawley rats were rendered insulin resistant by high fat feeding and diabetic by a single dose of streptozotocin (STZ). Diabetic rats were treated for 8 weeks with insulin, metformin or rosiglitazone, starting from either 1 week (prevention) or 8 weeks (reversal) after STZ administration. Sympathetic neuronal integrity was evaluated longitudinally by [11C]HED PET. Echocardiography measures of systolic and diastolic function were completed at serial timepoints. Plasma NE levels were evaluated serially and expression of NET and β-adrenoceptors were tested at the terminal endpoints. Diabetic rats exhibited a 52-57% reduction of [11C]HED standardized uptake value (SUV) at 8 weeks after STZ, with a parallel 2.5-fold elevation of plasma NE and a 17-20% reduction in cardiac NET expression. These findings were confirmed by ex vivo biodistribution studies. Transmitral pulse wave Doppler echocardiography established an extension of mitral valve deceleration time and elevated early to atrial velocity ratio, suggesting diastolic dysfunction. Subsequent treatment with insulin but not metformin restored glycemia, reduced plasma NE by 50%, normalized NET expression, and recovered [11C]HED SUV towards non-diabetic age-matched control. Diastolic dysfunction in these rats persisted. By contrast, early treatment with insulin, metformin, or rosiglitazone delayed the progression of diastolic dysfunction, but had no effect on elevated NE and reduced [11C]HED SUV in diabetic rats, potentially owing to a latent decrease in blood glucose. In conclusion, diabetes is associated with heightened circulating and tissue NE levels which can be effectively reversed by lowering glycemia with insulin. Noninvasive interrogation of sympathetic neuronal integrity using [11C]HED PET may have added value in the stratification of cardiovascular risk among diabetic patients and in determining the myocardial effects of glycemic therapy.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成5年2月19日 竹中晃氏の博士論文として提出された

No description available.

Speckle tracking echocardiography (STE) is a relatively new imaging modality that enables the direct measurement of active contractile myocardial tissue in an offline analysis. This is accomplished through a software algorithm that tracks collections of acoustic markers, known as 'speckles', that are unique to a given section of myocardium. By measuring the displacement of these 'speckles' as the heart contracts and relaxes, STE produces parameters of the strain, or percent change in length, exhibited by the myocardium. As multiple studies have shown, this strain data produced by tracking of the global left atrium has the ability to accurately assess the physiologic functions of the atrium as a reservoir, conduit and booster pump in the cardiac cycle. Despite these valuable correlations, there are noted problems with STE regarding acoustic cluttering and disappearance of 'speckles' that can occur as the selected region of interest moves out of the field of view or becomes obscured. These problems may be increased when tracking an extended region of myocardium. Therefore, this present study sought to test a new method of assessing left atrial function with STE strain analysis by focusing on a concise region of the atrium, specifically the interatrial septum. To test this, the echocardiograms of 37 patients were obtained and grouped according to the designation of their cardiac function as normal (n=11), abnormal (n=12), or exhibiting signs of cardiac amyloidosis (n=14). In all patients, STE strain analysis was performed on the both the global left atrium and the interatrial septum. Measurements of the mean peak strain observed in the resultant strain curves were recorded for both STE scans of each patient. The curves produced by the tracking the segments of the entire atrium (6 segments) and interatrial septum (3 segments) were compared based on the exhibited changes in strain seen in the relative shapes of the curves, as well as the spread of the segmental strain curves about the calculated mean strain curve. Additionally, the number of segments that were either unsuccessfully or incorrectly tracked was recorded as a measure of the accuracy of STE. As a final step, the interatrial strain curves of four selected patients in the various states of ventricular diastolic dysfunction were chosen and compared with data obtained from scans of mitral flow echocardiography and tissue Doppler imaging (TDI) in an attempt to correlate the exhibited changes in strain shown in the interatrial septum with the physiologic functions of the atrium during ventricular diastole. The results showed that the mean peak strain of the global atrial strain trace decreased from normal (41.32%±10.8) to abnormal (21.69%±13.8) to the amyloid group (10.41%±6.9). This trend was echoed in the mean peak strain measured in the interatrial septum, as measured in normal (64.2%±15.6), abnormal (28.37%±13.4) and amyloid groups (12.21%±12.1). When the strain curves of the entire atrium and interatrial septum were compared, they demonstrated similar patterns in the timing of changes in strain, however the strain curves of the individual interatrial septum segments showed a much more concise grouping about the mean strain curve and were less likely to exhibit discordant segmental strain curves that deviated from the pattern established by all other segments in the trace. Additionally, within the STE scans of the global atrium, the interatrial septum exhibited a higher percentage of successfully tracked segments than did the lateral atrial wall; this trend was universally exhibited in all three groups. Finally, the interatrial septum strain curves, mitral flow echocardiography and TDI scans all demonstrated similar indications of left atrial function in the four selected patients. Ultimately, STE strain analysis of the interatrial septum appears to be a more accurate method of tracking the atrial myocardium than STE tracing of the global left atrium. Furthermore, it shows viable potential as a method for assessing the global physiologic function of the left atrium, as indicated by the similarities between the trends exhibited by these STE scans and the data gathered from scans produced by mitral flow echocardiography and TDI.

Em pacientes com insuficiência cardíaca crônica podemos observar um aumento da atividade inflamatória, caracterizada por aumento de proteínas de fase ativa, citocinas circulantes e ativação de células do sistema imune. É descrito também que o exercício físico beneficia esses pacientes, porém ainda não está claro se esse benefício ocorre através da modulação do processo inflamatório no sistema cardiovascular. Assim, o objetivo deste estudo foi investigar, em pacientes com insuficiência cardíaca, o efeito do treinamento físico sobre a disfunção ventricular, avaliada pelo quadro clínico e ecocardiograma, e sobre vias de sinalização envolvidas no processo inflamatório cardiovascular, como CD40/CD40L, IL-6, TNF-alfa e PPARs. Foram selecionados dezoito pacientes com diagnóstico de IC, todos classificados com classe funcional II, com idade 57,17±2,9 anos. Os pacientes foram randomizados em dois grupos: grupo controle, que permaneceu sedentário e grupo treino, onde os pacientes foram treinados três vezes por semana, em cicloergômetro, durante 60 minutos por quatro meses. Os marcadores inflamatórios plasmáticos, CD40L, IL-6, TNF-alfa foram dosados por ELISA e a expressão de mRNA de CD40 e PPARs alfa e y em leucócitos circulantes pela técnica de RT-PCR. A função cardíaca foi avaliada pelo ecocardiograma, e a capacidade funcional foi avaliada através da ergoespirometria. Os pacientes submetidos ao treinamento físico apresentaram significante aumento do VO2 , comparados ao grupo controle (17,52±1,47 vs 21,14±0,86, respectivamente; p<0,05). Também foi observada melhora da função ventricular diastólica e manutenção da fração de ejeção do ventrículo esquerdo, que piorou nos pacientes mantidos sedentários (controle (38,00±3,37 vs 36,44±3,38, respectivamente; p<0,05). Em relação às vias de sinalização inflamatórias, não houve diferença em nenhum dos marcadores estudados (níveis plasmáticos de IL-6, TNF-alfa e CD40L e na expressão de mRNA de CD40 e PPARs alfa e y em leucócitos circulantes) quando comparados o grupo treinado ao controle. Conclui-se que o treinamento físico é efetivo na melhora da capacidade funcional e função cardíaca e que a atividade inflamatória característica nesses pacientes não está associada com essas mudanças. / Patients with chronic heart failure present increased inflammatory activity, characterized by high levels of active phase proteins and cytokines, as well as activated immune cells. Physical training is reported to be beneficial for these patients, however, it is not clear whether this benefit occurs thorough modulation of the inflammatory process that the cardiovascular system. Therefore, the main objective of this study was to investigate, in patients with chronic heart failure, the effect of physical training on ventricular dysfunction, assessed by clinical exam and echocardiography, as well as on signaling pathways involved in the cardiovascular inflammatory process, like CD40/CD40L, IL-6, TNF and PPARs. Eighteen patients diagnosed with chronic heart failure, functional class II, were selected (age=57,17±2,9). They were randomly divided in two groups: a control group and a trained group, whose patients were submitted to physical training for 4 months, 3 times/week, for 60 min, in a cycle ergometer. Plasmatic cytokines and CD40L were measured by ELISA; mRNA for CD40 and PPARs alfa / y were measured by RT-PCR in circulating leukocytes. Cardiac function was evaluated by echocardiography and functional capacity by ergospirometry. Patients submitted to physical training presented a significant increase in VO2 , compared to control group (17,52±1,47 vs 21,14±0,86 , respectively; p<0,05). Improvement in diastolic ventricular function was also observed , as well as maintenance of left ventricular ejection fraction , that was impaired in patients in the control group (38,00±3,37 vs 36,44±3,38, respectively; p<0,05). Regarding the inflammatory signaling pathways, no difference was observed in any of the markers evaluated (plasmatic levels of IL6, TNF, CD40L and expression of mRNA for CD40 and PPARs alfa / y in circulating leukocytes). Therefore, we can conclude that physical training is effective in improving functional capacity and cardiac function in patients with chronic failure; this phenomenon is unlikely to be related to modulation of inflammatory signaling pathways characteristic of cardiovascular diseases.

Diagnosis of diabetes mellitus, presence of hyperglycemia, and/or insulin resistance confer cardiovascular risk, particularly for diastolic dysfunction. Diabetes is associated with elevated myocardial norepinephrine (NE) content, enhanced sympathetic nervous system (SNS) activity, altered resting heart rate, and depressed heart rate variability. Positron emission tomography (PET) using the NE analogue [11C]meta-hydroxyephedrine ([11C]HED) provides an index of myocardial sympathetic neuronal integrity at the NE reuptake transporter (NET). The hypothesis of this project is that (i) hyperglycemia imparts heightened sympathetic tone and NE release, leading to abnormal sympathetic neuronal function in the hearts of diabetic rats, and (ii) these abnormalities may be reversed or prevented by treatments to normalize glycemia. Sprague Dawley rats were rendered insulin resistant by high fat feeding and diabetic by a single dose of streptozotocin (STZ). Diabetic rats were treated for 8 weeks with insulin, metformin or rosiglitazone, starting from either 1 week (prevention) or 8 weeks (reversal) after STZ administration. Sympathetic neuronal integrity was evaluated longitudinally by [11C]HED PET. Echocardiography measures of systolic and diastolic function were completed at serial timepoints. Plasma NE levels were evaluated serially and expression of NET and β-adrenoceptors were tested at the terminal endpoints. Diabetic rats exhibited a 52-57% reduction of [11C]HED standardized uptake value (SUV) at 8 weeks after STZ, with a parallel 2.5-fold elevation of plasma NE and a 17-20% reduction in cardiac NET expression. These findings were confirmed by ex vivo biodistribution studies. Transmitral pulse wave Doppler echocardiography established an extension of mitral valve deceleration time and elevated early to atrial velocity ratio, suggesting diastolic dysfunction. Subsequent treatment with insulin but not metformin restored glycemia, reduced plasma NE by 50%, normalized NET expression, and recovered [11C]HED SUV towards non-diabetic age-matched control. Diastolic dysfunction in these rats persisted. By contrast, early treatment with insulin, metformin, or rosiglitazone delayed the progression of diastolic dysfunction, but had no effect on elevated NE and reduced [11C]HED SUV in diabetic rats, potentially owing to a latent decrease in blood glucose. In conclusion, diabetes is associated with heightened circulating and tissue NE levels which can be effectively reversed by lowering glycemia with insulin. Noninvasive interrogation of sympathetic neuronal integrity using [11C]HED PET may have added value in the stratification of cardiovascular risk among diabetic patients and in determining the myocardial effects of glycemic therapy.

Increasing diastolic dysfunction (DD) grade is associated with increased heart failure (HF). Patients with preserved ejection fractions and grade 1 DD may have left atrial dilatation, e′ < 8 cm/sec, increased left ventricular (LV) mass, or variable E/e′ ratios. The aim of this study was to test the hypothesis that LV hypertrophy or E/e′ ratio > 8 may be associated with a greater incidence of HF. Methods Two hundred twelve patients with grade 1 DD and ejection fractions > 50% were retrospectively studied. Group 1 comprised 108 patients with E/A ratios < 0.8, without LV hypertrophy, e′ < 8 cm/sec, and E/e′ ratios < 8. Group 2 comprised 104 patients with LV hypertrophy or E/e′ ratios > 8. Patients with incident HF and valvular or coronary disease were excluded. Using two-dimensional Doppler echocardiography, LV and left atrial volumes and transmitral spectral and tissue Doppler were analyzed. Medical records were examined for laboratory data, HF admissions, and all-cause mortality from 2004 to 2012. Results Despite similar ejection fractions, patients in group 2 had greater LV and left atrial volumes, LV mass index values, and E/e′ ratios (P < .01 for all). HF incidence was greater in group 2 (30 vs 4, P < .001). Combined HF or all-cause mortality was greater in group 2 (46 vs 14, P < .001). Multivariate analysis revealed that HF was associated with E/e′ ratio (P < .0001), systolic blood pressure (P = .0123), and LV mass index (P = .042). Combined HF or all-cause mortality was associated with E/e′ ratio (P < .0001), LV mass index (P = .009), and lower calcium channel blocker use (P = .0011). Conclusions HF alone or HF and all-cause mortality were increased in patients with grade 1 DD in the presence of LV hypertrophy or elevated LV filling pressures.

Diabetes causes cardiomyopathy and increases the risk of heart failure independent of hypertension and coronary heart disease. This condition called “Diabetic Cardiomyopathy” (DCM) is becoming a well- known clinical entity. Recently, there has been substantial research exploring its molecular mechanisms, structural and functional changes, and possible development of therapeutic approaches for the prevention and treatment of DCM. This review summarizes the recent advancements to better understand fundamental molecular abnormalities that promote this cardiomyopathy and novel therapies for future research. Additionally, different diagnostic modalities, up to date screening tests to guide clinicians with early diagnosis and available current treatment options has been outlined.

Left ventricular diastolic dysfunction (LVDD) is any abnormality in the filling of the left ventricle (LV).  Despite the prevalence of this disease, it remains difficult to diagnose, mainly due to inherent compensatory mechanisms and a limited physical understanding of the filling process.  LV filling can be non-invasively imaged using color m-mode echocardiography which provides a spatio-temporal map of inflow velocity.  These filling patterns, or waves, are conventionally used to qualitatively assess the filling pattern, however, this work aims to physically quantify the filling waves to improve understanding of diastole and develop robust, reliable, and quantitative parameters. This work reveals that LV filling waves in a normal ventricle act as dispersive waves and not only propagate along the length of the LV but also spread and disperse in the direction of the apex.  In certain diseased ventricles, this dispersion is limited due to changes in LV geometry and wall motion.  This improved understanding could aid LVDD diagnostics not only for determining health and disease, but also for distinguishing between progressing disease states. This work also identifies a limitation in a current LVDD parameter, intra ventricular pressure difference (IVPD), and presents a new methodology to address this limitation.  This methodology is also capable of synthesizing velocity information from a series of heartbeats to generating one representative heartbeat, addressing inaccuracies due to beat-to-beat variations.  This single beat gives a comprehensive picture of that specific patient's filling pattern.  Together, these methods improve the clinical utility of IVPD, making it more robust and limiting the chance for a misdiagnosis. / Master of Science