No description available.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Objective The objective of this study was to investigate the effect of preoperative diastolic dysfunction on postoperative mortality and morbidity after cardiovascular surgery. Methods We systematically searched for articles that assessed the prognostic role of diastolic dysfunction on cardiovascular surgery in PubMed, Cochrane Library, Web of Science, Embase and Scopus until February 2016. Twelve studies (n=8224) met our inclusion criteria. Due to scarcity of outcome events, fixed-effects meta-analysis was performed using the Mantel-Haenszel method. Results Preoperative diagnosis of diastolic dysfunction was associated with higher postoperative mortality (OR 2.41, 95% CI 1.54-3.71; p<0.0001), major adverse cardiac events (MACE) (OR 2.07, 95% CI 1.55-2.78; p <=0.0001) and prolonged mechanical ventilation (OR 2.08, 95% CI 1.04-4.16; p=0.04) in comparison to patients without diastolic dysfunction among patients who underwent cardiovascular surgery. The odds of postoperative myocardial infarction (OR: 1.29, 95% CI 0.82, 2.05; p=0.28) and atrial fibrillation (OR: 2.67; 95% CI 0.49-14.43; p=0.25) did not significantly differ between the two groups. Severity of preoperative diastolic dysfunction was associated with increased postoperative mortality (OR 21.22, 95% CI 3.74 -120.33; p=0.0006) for Grade 3 diastolic dysfunction compared with patients with normal diastolic function. Inclusion of left ventricular ejection fraction (LVEF) <40% accompanying diastolic dysfunction, did not further impact postoperative mortality (p=0.27; I2 =18%) when compared with patients with normal LVEF and diastolic dysfunction. Conclusions Presence of preoperative diastolic dysfunction was associated with higher postoperative mortality and MACE, regardless of LVEF. Mortality was significantly higher in grade III diastolic dysfunction. Keywords Diastolic dysfunction; cardiovascular surgical procedures; mortality; meta-analysis / Revisión por pares

Recent studies support the association between metabolic syndrome (MetS), a cluster of cardiovascular risk factors, and diastolic dysfunction. Disproportionate collagen accumulation, particularly cross-linking of collagen, plays a key role in translating interstitial fibrosis into mechanical chamber stiffness and diastolic dysfunction. Characteristic changes in the expression and activity of myocardial lysyl oxidase (LOX), a matrix modifying enzyme that catalyzes cross-linked collagen, are unclear in MetS. We established a diet-induced MetS model to study diastolic dysfunction by treating male C57BL/6 mice a high-fat high-simple carbohydrate (HFHSC) diet for 6 months. Despite blunted gene expression of LOX isoforms, MetS mice demonstrated significant increase in the ratio of protein expression of mature to proenzyme LOX, enhanced LOX activity, and increased cardiac cross-linked collagen compared with controls. This fibrotic response coincided with marked increase in left ventricular end-diastolic pressure and stiffness and impaired diastolic filling pattern. Our data demonstrate that diet-induced MetS alters the remodeling enzyme LOX, thereby increasing the amount of crosslinking and inducing diastolic dysfunction.Furthermore we examined the role of T-lymphocytes in myocardial LOX regulation in diet-induced fibrotic hearts. Female SCID mice which are devoid of functional T-lymphocytes and C57BL/6 mice were treated with HFHSC diet for 12 months. Similar to male C67BL/6, female HFHSC-fed C57BL/6 mice demonstrated significant increase in maturation and catalytic activity of myocardial LOX, cross-linking, ventricular stiffness and diastolic dysfunction. Whereas induction of LOX protein was minimal in SCID mice compared with wild-type counterparts. Correspondingly fibrillar cross-linked collagen formation and diastolic dysfunction were less prominent in SCID mice. Our results suggest a potential role of T-lymphocytes in induction of myocardial stiffness and diastolic dysfunction through modulation of LOX-dependent collagen maturation.Moreover we studied the role of leptin, an adipokine over-produced in MetS with fibrotic effects in non-cardiac tissues, as a key mediator of profibrogenic responses in the heart by administrating leptin to C57BL/6 and leptin-deficient ob/ob mice. With exogenous leptin administration ob/ob mice displayed passive diastolic filling dysfunction that coincided with increase in myocardial collagen compared with ob/ob controls. Our findings suggest profibrotic effects of leptin in the heart, primarily through predominance of collagen synthesis over degradation.

Background Right ventricular (RV) diastolic function has been associated with outcomes for patients with pulmonary hypertension; however, the relationship between biomechanics and hemodynamics in the right ventricle has not been studied. Methods and Results Rat models of RV pressure overload were obtained via pulmonary artery banding (PAB; control, n=7; PAB, n=5). At 3 weeks after banding, RV hemodynamics were measured using a conductance catheter. Biaxial mechanical properties of the RV free wall myocardium were obtained to extrapolate longitudinal and circumferential elastic modulus in low and high strain regions (E-1 and E-2, respectively). Hemodynamic analysis revealed significantly increased end-diastolic elastance (E-ed) in PAB (control: 55.1 mm Hg/mL [interquartile range: 44.785.4 mm Hg/mL]; PAB: 146.6 mm Hg/mL [interquartile range: 105.8155.0 mm Hg/mL]; P=0.010). Longitudinal E1 was increased in PAB (control: 7.2 kPa [interquartile range: 6.718.1 kPa]; PAB: 34.2 kPa [interquartile range: 18.144.6 kPa]; P=0.018), whereas there were no significant changes in longitudinal E-2 or circumferential E-1 and E-2. Last, wall stress was calculated from hemodynamic data by modeling the right ventricle as a sphere: (stress = Pressure x radius/2 x thickness Conclusions RV pressure overload in PAB rats resulted in an increase in diastolic myocardial stiffness reflected both hemodynamically, by an increase in E-ed, and biomechanically, by an increase in longitudinal E-1. Modest increases in tissue biomechanical stiffness are associated with large increases in E-ed. Hemodynamic measurements of RV diastolic function can be used to predict biomechanical changes in the myocardium.

Introduction: Hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder of the cardiac sarcomere, resulting in myocyte hypertrophy and disarray, interstitial fibrosis, and cardiac dysfunction. Our aim was to determine whether the amount of fibrosis in HCM correlates with echocardiographic measures of diastolic dysfunction, presence of HCM-susceptibility mutations, or polymorphisms in the renin-angiotensin-aldosterone system (RAAS). Methods: Surgical specimens from patients with obstructive HCM undergoing septal myectomy at the Mayo Clinic (2001-2004) were examined and compared with autopsy-derived tissues from age- and sex-matched normal controls. Digital image analysis was used to quantitate the fibrosis in representative microscopic sections. Genotyping was performed for myofilament-HCM using polymerase chain reaction, high-performance liquid chromatography, and direct DNA sequencing. RAAS polymorphism status was similarly established. Results: The study included 59 HCM cases and 44 controls. Patients with HCM exhibited more fibrosis (mean 17%, range 3-45%) than controls (mean 8%, range 3-17%) (P<.0001). A significant relationship existed between amount of fibrosis and maximum wall thickness (P=.02), left ventricular ejection fraction (P=.02), and peak early/late diastolic mitral annulus velocity (E/A ratio) (P=.002). Although there was no association between amount of fibrosis and myofilament-HCM genotype status or polymorphisms in the RAAS cascade, there was a trend toward more fibrosis in patients with ≥1 C-encoding allele in CYP11B2-encoded aldosterone synthase. Conclusions: Patients with HCM undergoing septal myectomy had significantly more myocardial interstitial fibrosis than controls. The amount of fibrosis in HCM patients correlated with degree of septal hypertrophy and left ventricular systolic and diastolic function. Notably, neither mutations in cardiac myofilament proteins or polymorphisms in RAAS exhibited strong associations with severity of myocardial fibrosis.

No description available.

Objective: We sought to determine N-terminal proatrial natriuretic peptide concentrations [Nt-proANP] in plasma from cats with hypertrophic cardiomyopathy (HCM). Secondarily, we wished to evaluate the relationship between [Nt-proANP] and echocardiographic variables. Methods: Venous blood samples were obtained from seventeen cats with HCM and from nineteen healthy cats. Plasma [Nt-proANP] was determined using an ELISA assay. The relationship between plasma [Nt-proANP] and M-mode, 2-dimensional and Doppler echocardiographic variables was evaluated. Cats that were hyperthyroid or had evidence of renal disease were excluded from the study. Results: The mean plasma [Nt-proANP] was higher in cats with HCM (3.81 +/- 1.23 pmol/l) than in control cats (3.08 +/- 1.41 pmol/l); however, this difference was not statistically significant (p=0.17). There was a significant correlation between plasma [Nt-proANP] and left ventricular posterior wall thickness (r = 0.42; p=0.01). Additionally, plasma [Nt-proANP] was correlated with left atrial size (r = 0.35; p=0.03). A linear regression model was developed to further explore these relationships. LAs2D and LVPWd had an interactive effect on plasma [Nt-proANP] (R2 = 0.2737; p= 0.02). There was no correlation between any other echocardiographic variable and plasma [Nt-proANP]. There was no correlation between plasma [Nt-proANP] and heart rate (HR), body-weight, or age. Conclusions: Cats with HCM do not have significantly higher plasma [Nt-proANP] than normal cats. There was a significant linear relationship between [Nt-proANP] and LAs2D, LVPWd and the model that described their interaction. / Master of Science

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.

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.

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.