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.

Understanding cardiac pumping function is crucial to guiding diagnosis, predicting outcomes of interventions, and designing medical devices that interact with the cardiovascular system.  Computer simulations of hemodynamics can show how the complex cardiovascular system is influenced by changes in single or multiple parameters and can be used to test clinical hypotheses. In addition, methods for the quantification of important markers such as elevated arterial stiffness would help reduce the morbidity and mortality related to cardiovascular disease. The general aim of this thesis work was to improve understanding of cardiovascular physiology and develop new methods for assisting clinicians during diagnosis and follow-up of treatment in cardiovascular disease. Both computer simulations and medical imaging were used to reach this goal. In the first study, a cardiac model based on piston-like motions of the atrioventricular plane was developed. In the second study, the presence of the anatomical basis needed to generate hydraulic forces during diastole was assessed in heathy volunteers. In the third study, a previously validated lumped-parameter model was used to quantify the contribution of arterial and cardiac changes to blood pressure during aging. In the fourth study, in-house software that measures arterial stiffness by ultrasound shear wave elastography (SWE) was developed and validated against mechanical testing. The studies showed that longitudinal movements of the atrioventricular plane can well explain cardiac pumping and that the macroscopic geometry of the heart enables the generation of hydraulic forces that aid ventricular filling. Additionally, simulations showed that structural changes in both the heart and the arterial system contribute to the progression of blood pressure with age. Finally, the SWE technique was validated to accurately measure stiffness in arterial phantoms. / <p>QC 20161115</p>

Takotsubo cardiomyopathy (TTC) is a disease characterized by transient left ventricular (LV) dysfunction and typical wall motion abnormalities in apical parts, without obvious signs of coronary influence. Due to its elusive natural cause and the lack of clarified pathology, further studies are needed. Thirteen patients presented with an episode of TTC, and referred to Örebro University Hospital (USÖ), were prospectively included and investigated by comparisons made at onset (acute phase) against at follow-up three months later (recovery phase). Including echocardiographic measurements, focused on biventricular systolic long-axis function and conventional diastolic function (DF) variables. Systolic improvement was shown, while most DF data were unchanged, suggesting that TTC is mainly a systolic disease affecting both ventricles. Diagnosis should include multidisciplinary engagement, as TTC associates both with emotional stress and pathological markers of physiological stress. In this thesis, such approach was offered to the aforementioned patients; to see if a common denominator could be found, thus, contributing to better handling. Emotional state was assessed, along with an array of cardiac investigations in addition to echocardiography. Acutely, imbalance in the autonomic cardiac control was shown, as well as a trend toward posttraumatic stress, but specific findings allowing conclusions on differential diagnosis could not be demonstrated. By adding another 15 TTC patients (i.e. 28 in total), through collaboration with observers from USA, a retrospective echocardiographic analysis could be done to further study DF; concluding that TTC associates with impairment of conventional DF variables which tends to parallel the systolic recovery, in contrary to the initial result but in line with other causesof LV dysfunction. Magnetic resonance imaging (MRI) is another method of choice at TTC. The USÖ patients had cardiac MRI, thus, a retrospective analysis was done to investigate the effect on LV geometry, both echocardiographic and by MRI; suggesting that TTC is consistently associated with increased LV mass, due to a local impact that seems to follow the change in LVconcentric wall motion.

O +dP/dt e o dP/dt são considerados índices ecocardiográficos de avaliação da função sistólica e diastólica, respectivamente, menos influenciados pela pré e pós-carga do que os índices calculados na fase de ejeção. O objetivo desse estudo foi determinar se o dP/dt não-invasivo se correlaciona com os índices ecocardiográficos sistólicos e diastólicos e se pode ser usado para identificar animais com e sem remodelamento, aqueles com e sem ICC e avaliar a gravidade da DVCM. Esta pesquisa constituiu um estudo clínico observacional prospectivo transversal, realizada em cães com DVCM. Comparou-se o +dP/dt e o dP/dt entre grupos divididos quanto à presença de remodelamento e presença ou não de ICC; para a comparação do dP/dt em relação à função diastólica do VE, os cães foram distribuídos de acordo com o padrão diastólico. Os cães foram submetidos ao exame ecodopplercardiográfico para mensuração do +dP/dt, -dP/dt e dos demais índices ecocardiográficos. Foram inclusos ao todo 57 cães com DVCM, em estágios B1 (n=13), B2 (n=18) e C+D (n=26). Comparando-se o +dP/dt nos três grupos divididos de acordo com à presença de remodelamento, com ou sem ICC, o grupo C+D (2142 mmHg/s, P25-P75 = 2023-2456) apresentou +dP/dt significativamente mais baixo que o grupo B1 (2865 mmHg/s, P25-P75 = 2383-3308) e B2 (2721 mmHg/s, P25-P75 = 2241-3186) (P = 0,0023). O mesmo foi observado para o dP/dt, quando comparado o grupo C+D ao grupo B1 (968,5 mmHg/s ± 266,8 e 1198 mmHg/s ± 165,7; P= 0,0115). Quando o dP/dt foi comparado entre os grupos com ICC e sem ICC, o grupo com ICC apresentou valores menores tanto do +dP/dt (2142 mmHg/s, P25-P75 = 2023-2456; 2858 mmHg/s, P25-P75 = 2299-3241; P = 0,0007) como do dP/dt (968,5 ± 266,8 mmHg/s e 1155 mmHg/s ± 199,0; P = 0,0041). Quanto à função diastólica, o grupo com padrão restritivo (769,7 mmHg/s ± 124,1) apresentou valores menores do -dP/dt quando comparados aos grupos sem disfunção diastólica (1132 mmHg ± 204,0), alteração de relaxamento (1229 mmHg ±186,9) e padrão pseudonormal (1107 mmHg ±223,4) (P&lt; 0,0001). Utilizando-se +dP/dt&lt;1800 mmHg/s como ponto de corte, houve duas vezes mais chance do cão com DVCM ter ICC do que não ter. Considerando-se como ponto de corte um -dP/dt&lt;800mmHg/s, a chance de ter ICC é oito vezes maior do que não ter e a chance de ter padrão diastólico restritivo é oito vezes maior do que não ter. Conclui-se que o +dP/dt e o dP/dt não-invasivos podem contribuir, respectivamente, para a avaliação da função sistólica e diastólica. / Noninvasive +dP/dt and dP/dt derived from mitral regurgitant jet are considered echocardiographic indexes for assessment of systolic and diastolic function respectively, that have less preload and afterload dependence than the ejection phase indexes. This study aimed to determine whether non-invasive dP/dt correlates with other systolic and diastolic echocardiographic indexes, and if they can be used to identify dogs with and without remodeling, with or without congestive heart failure (CHF) and for evaluation of chronic mitral valve disease (CMVD) severity. An observational prospective cross-sectional clinical study was undertaken including dogs with CMVD. Dogs were distributed in groups regarding the presence of remodeling and heart failure,to evaluate +dP/dt and dP/dt, and distributed according the diastolic pattern to compare dP/dt regarding diastolic function. Echocardiographic exam was obtained for conventional indexes and to measure +dP/dt and -dP/dt. Fifty seven dogs diagnosed with CMVD and classified according to the stages [B1 (n=13), B2 (n=18), C+D (n=26)] were included. In the comparison among the three groups regarding the presence of remodeling and CHF, group C+D (2142 mmHg/s, P25-P75 = 2023-2456) had +dP/dt significantly lower than B1 (2865 mmHg/s, P25-P75 = 2383-3308) and B2 (2721 mmHg/s, P25-P75 = 2241-3186) (P = 0.0023). Group C+D also had lower dP/dt, compared to B1 (968.5 mmHg/s ± 266.8 and 1198 mmHg/s ± 165.7; P= 0.0115). Group of dogs with CHF compared to those without CHF, showed lower +dP/dt (2142 mmHg/s, P25-P75 = 2023-2456; 2858 mmHg/s, P25-P75 = 2299-3241; P = 0.0007) as well as dP/dt (968.5 ± 266.8 mmHg/s e 1155 mmHg/s ± 199.0; P=0.0041). Regarding diastolic function, -dP/dt was lower for the restrictive pattern group (769.7 mmHg/s ± 124.1) compared to those without diastolic disfunction, (1132 mmHg ± 204.0), relaxation abnormality (1229 mmHg ±186.9) and pseudonormal pattern (1107 mmHg ±223.4) (P&lt; 0.0001). Considering +dP/dt&lt1800 mmHg/s as cutoff value, there is twice the chance for the dog with CMVD to have CHF than not to have. With a -dP/dt&lt;800mmHg/s as a cut off value, the chance of having CHF is eigth times higher than not having it. It is concluded that non-invasive doppler derived +dP/dt and dP/dt may contribute respectively, for systolic and diastolic assessment of dogs with CMVD.

Orientador: Paulo Sergio Patto dos Santos / Resumo: A lidocaína é um fármaco versátil muito utilizado na rotina clínica. No entanto, há poucos estudos que avaliam os seus efeitos sobre o coração. Para esta finalidade, a ecocardiografia transtorácica é uma ferramenta que possibilitava a avaliação das funções sistólica e diastólica em tempo real. Como este estudo, objetivou-se avaliar os efeitos da infusão contínua de lidocaína sobre as funções sistólica e diastólica do ventrículo esquerdo de coelhos hígidos sedados com midazolam. Para tanto, foram utilizados dez coelhos da raça Nova Zelândia, quatro machos e seis fêmeas, com idade de nove meses, pesando 3,2 ± 0,3 kg, sendo todos os animais sedados com midazolam na dose de 1 mg/kg pela via intramuscular e submetidos a dois tratamentos experimentais (controle e lidocaína) com intervalo mínimo de sete dias entre os tratamentos. No tratamento controle (TC) administrou-se solução de cloreto de sódio a 0,9% (0,05 mL/kg) em bolus seguida de infusão contínua na taxa de 5 mL/hora; no tratamento lidocaína (TL) administrou-se primeiramente um bolus de lidocaína a 2% sem vasoconstritor na dose de 1 mg/kg seguido de infusão contínua na taxa de 50 µg/kg/minuto, sendo mantidos os mesmos volumes administrados para ambos os tratamentos. As principais variáveis analisadas foram: frequência cardíaca (FC), pressão arterial média (PAM), índice de resistência vascular periférica (IRVP), índice cardíaco Doppler (ICD), fração de encurtamento (FEC), fração de ejeção (FEJ), velocidade da onda S′ e relaç... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Lidocaine is a versatile drug widely used in clinical practice. However, there are few studies that evaluate its effects on the heart. For this purpose, transthoracic echocardiography is a tool that allows an evaluation of the systematic and diastolic units in real time. The aim of the study was evaluate the effects of continuous rate infusion of lidocaine on systolic and diastolic functions of the left ventricle of healthy rabbits sedated with midazolam. Ten New Zealand rabbits, four males and six females, aged nine months, weighing 3.2 ± 0.3 kg were sedated with midazolam at the dose of 1 mg/kg intramuscularly and submitted to two experimental treatments (control and lidocaine) with a minimum interval of seven days. In the control treatment (CT), 0.9% sodium chloride solution (0.05 mL.kg-1 ) was administered in bolus followed by continuous infusion at a rate of 5 mL.hour-1 ; a 2% lidocaine bolus without vasoconstrictor at the dose of 1 mg.kg-1 followed by continuous infusion at the rate of 50 μg.kg-1 .minute-1 was first given in lidocaine treatment (LT). The main variables analyzed were: heart rate (HR), mean arterial pressure (MAP), peripheral vascular resistance index (PVR), Doppler cardiac index (DCI), shortening fraction (FEC), ejection fraction (EFJ), velocity of the wave S 'and relation E'/A'. All parameters were evaluated before the onset of the bolus (MB) and 20, 40 and 60 minutes after the start of continuous rate infusion (M20, M40 and M60). The studied variables ... (Complete abstract click electronic access below) / Mestre

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.

Assessment of left ventricular (LV) function is one of the most common requests made to cardiac imaging services. This demand stems from a large body of evidence that shows abnormal LV systolic and, more recently, diastolic function has important prognostic and treatment related implications for patients with a wide range of cardiovascular diseases. The vast majority of information supporting the use of conventional measures of LV function, such as ejection fraction, originates from population studies and large clinical trials. However, the application of these measurements to individual patients is far less defined, especially when used for serial evaluation. Central to these concerns is the relative paucity of data surrounding the test-retest reliability of conventional measures in clinical settings. Newer measures of LV function have been developed over recent years, with several techniques becoming widely used in clinical practice (i.e. tissue Doppler imaging) and others remaining largely research tools (i.e. 3D echocardiography, tissue strain/strain rate). Possible benefits of new technologies include improved identification and early detection of myocardial disease, improved reliability for monitoring progression of disease, and the development of novel methods to assess response to therapy. Despite this potential, the application and clinical utility of these techniques above and beyond more conventional measures remains in many cases to be adequately characterized. This thesis addresses several of these issues: from variability of novel and conventional measures of LV function in clinical practice, to new applications of novel functional measures in clinical settings.

Large-scale modeling allows for a broad mechanistic view of a cardiopulmonary disease, often beyond what can be observed clinically. Our group has developed a large-scale model of the human cardiovascular-respiratory system (H-CRS) that integrates heart mechanics, hemodynamics, circulatory and gas transport aspects of the lung, brain and whole body tissue, and nervous system control of the cardiovascular and respiratory systems into a single model that can be used to analyze the dynamic behavior of the normal and deranged cardiopulmonary system. The model is a composite model based on data from multiple sources, developed over the years, and has been able to mimic responses to cardiovascular, respiratory, and nervous system activity, and accurately predict changes to environmental or diseased conditions. The ability of a large-scale model to portray many aspects of the cardiopulmonary system simultaneously is beyond the scope of clinical procedures, as providing such data becomes overly invasive, expensive, and risky. However, clinical questions can be pursued in virtual mode using modeling as a tool, and the hope is that modeling might also point to novel avenues to explore in disease diagnosis. In this work, we have advanced new conceptual framework of pericardial constraint, respiratory modulation, and septal pumping in the H-CRS model to address three important clinical topics. The first is cardiac tamponade (CT) which results from fluid accumulation in the pericardial sac; the second is left ventricular diastolic dysfunction (LVDD) which leads to congestive heart failure; the third is a hemodynamic analysis of the use of left ventricular rotary assist devices in systolic heart failure due to left ventricular systolic dysfunction (LVSD). These topics are highly relevant in the clinical setting, employ advanced methods for clinical diagnosis (with sufficient clinical data available for model validation), yet contain unanswered physiological questions for our modeling to explore. For example, the proposed modeling studies show that detailed mechanistic characterization of the diseases CT, LVDD, and LVSD exhibit model-generated results of known disease signs, but also reveal the significance of unexplored right heart symptoms and the important role of septal mechanics in these disease states. Left ventricular assist device (LVAD) modeling demonstrates improvement in cardiac output and reduced left heart work, but at the expense of septal functionality and right heart work. Our work in demonstrating the ability of a large-scale model to portray many complex aspects of the cardiopulmonary system simultaneously suggests that modeling might provide novel avenues to explore disease diagnosis, physiology, and management.

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.