Dissertationen zum Thema „Cardiac stiffness“

The giant sarcomeric protein titin spans the length of the half sarcomere and contains an I-band spanning region that functions as a molecular spring that develops passive force during diastole. Titin stiffness is modulated both by isoform switching and post-translational modifications including phosphorylation. Modulation of titin stiffness occurs in physiological and pathophysiological states including Heart Failure with Preserved Ejection Fraction (HFpEF) which is marked by increased diastolic stiffness. Here, I investigated the effects of titin phosphorylation by two kinases, ERK2 and CaMKIIδ, at the level of the protein and the myocardium. Additionally, I used mouse models of HFpEF to test if modulating titin stiffness could ameliorate increased diastolic stiffness. Specifically, I used the TAC/DOCA model (surgical) and the N2B KO model (genetic) of HFpEF to test the effects of metformin on titin stiffness and diastolic function. HFpEF mice treated with metformin had improved diastolic function, reduced passive stiffness, and increased PKA phosphorylation compared to non-treated HFpEF animals. Interestingly, these results were only found in animals with an intact N2B-element indicating an underlying mechanism that arises from the N2B element and that includes an increase in PKA-phosphorylation. Additionally, I used the TtnΔIAjxn mouse model, as a mechanical analog of the increased diastolic stiffness in HFpEF, to test the therapeutic effects of exercise and heart rate reduction. Exercise induced hypo-phosphorylation of the PEVK element of titin consistent with reduced passive tension while heart-rate reduction had no effect on passive stiffness. These studies build on the increasing understanding of how titin's stiffness can be modulated and the ways to take advantage of titin in a beneficial manner for diastolic function.

"The stiffness of scaffolds used in surgical ventricular restoration may play an important role in the degree to which they facilitate regeneration of functional cardiac tissue. The stiffness of the scaffold influences the phenotype of cells which are present in it as well as their ability to deform the scaffold. The goal of this study was to evaluate in vitro methods to characterize and alter the stiffness of new scaffold materials. Membrane inflation testing, an in vitro mechanical testing method, was evaluated in this study because of its ease of use and the similar mode of loading which it shares with scaffolds implanted in vivo. The structural stiffness of two scaffold materials, urinary bladder matrix and Dacron, were determined in vivo and using membrane inflation testing. Despite higher tensions and lower area stretch ratios for scaffolds tested using membrane testing, similar changes in structural stiffness between the two materials were found for both methods (5.6 ± 3.3 fold in vivo, 5.0 ± 1.0 in vitro). This finding demonstrated that membrane inflation testing is a useful in vitro method for measuring changes in structural stiffness between scaffold materials with a level of sensitivity similar to that which is measured in vivo. Membrane inflation testing was used to assess the effectiveness of altering scaffold stiffness through exposure to various cell culture conditions. Incubation of a biological membrane in cell culture media resulted in a drastic decrease in the elastic modulus from its initial value (3.55 ± 0.52 MPa) after 2 weeks (1.79 ± 0.30 MPa), 4 weeks (1.04 ± 0.09 MPa), and 10 weeks (0.014 ± 0.01 MPa). When fibroblasts were cultured on the scaffolds for 10 weeks an increase in elastic modulus (0.134 ± 0.05 MPa) over scaffolds incubated in culture media for the same amount of time was observed. The increase in elastic modulus due to the presence of fibroblasts was accompanied by an increase in the percentage of collagen in the samples (54.1 ± 5.1 % without fibroblasts, 83.2 ± 5.1 % with fibroblasts). Contrary to expectation, addition of ascorbic acid to the media to increase production of collagen by the fibroblasts resulted in a decrease in elastic modulus (0.030 ± 0.01 MPa) compared to scaffolds cultured with fibroblasts in standard media and a decrease in the amount of enzymatically degraded collagen (40.8 ± 4.7 % without ascorbic acid, 21.1 ± 3.3 % with ascorbic acid). Regeneration of cardiac tissue after a myocardial infarction is a complicated process which is influenced by a myriad of different factors. Future studies investigating the exact role which substrate stiffness has on regeneration will be essential to the development of improved cardiac scaffolds. Characterization of the stiffness of these scaffolds by membrane inflation and manipulation through exposure to cell culture conditions are powerful approaches to facilitate future studies."

In patients with atrial fibrillation (AF) there appears a close link between arterial stiffness, endothelial function and cardiac remodelling thereby contributing to the development and progression of AF as well as to its complications. However this complex interaction(s) is not well understood. In the cross-sectional study with PAF patients, higher arterial stiffness (PP, Pr) is strongly associated with endothelial-dependent macro-vascular dysfunction (Δ%AIx Salbutamol). Similarly a strong relationship observed between arterial stiffness (PP, PWV cf, Pr) and abnormal LA remodelling (LAV and LAD) in PAF patients. Higher levels of vWf and soluble E-Selectin at baseline are independently associated with increased risk of adverse clinical events (including AMI and ischaemic stroke) in ‘real world’ AF patients, and may aid clinical risk stratification towards identifying patients at higher risk. In the longitudinal study of dual chamber pacemaker patients there was a close relationship observed between arterial stiffness (PP, PWV cf, Pr), macro-vascular (Δ%AIx Sal) / micro-vascular (∆%LDF Ach) endothelial function and cardiac remodelling (EF, E/A ratio, E_M, A_M). These findings support the close interaction between ventricular contraction, arterial system and endothelial function towards the development of AF in pacemaker patients, beyond the adverse effects of pacing per se.

The quest for novel biomaterials to promote cell structural and functional maturation for cardiac tissue regeneration has emphasized a need to create microenvironments with physiological features. Substrate stiffness constitutes a structural property of crucial importance in the field of tissue engineering and many studies have shown how cardiac cells sense the rigidity of the substrate on which they grow. In this work, we focused on the relevance of substrates mimicking cardiac extracellular matrix (cECM) rigidity for the understanding of the complex interplay between the extracellular and intracellular compartments. Among the most promising biomaterials, Liquid Crystalline Elastomers (LCEs) represent a novel class of polymers previously investigated both as artificial muscles for biomedical purposes and dynamic cell scaffolds. The development of new smart materials which can provide bioactive cues to control and regulate cell fate has been recently encouraged. Indeed, mechanical cues play a significant role in maintaining cell and tissues/organs functions and, in this respect, cell models and substrate stiffness appear as intriguing tools for the investigation of cECM-cell interactions both in physiological and pathological conditions. From the perspective of materials, we have explored the fabrication of biomimetic patterned substrates to direct human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) growth and evaluate their effect on cell functional properties. In the field of regenerative medicine, the advent of hiPSC-CMs has paved the way for a patient-specific therapy but the development of more mature hiPSC-CMs is still needed. Promising approaches that have begun to be investigated include long-term culture, mechanical loading, 3-dimensional tissue engineering and, above all, the use of dynamic scaffolds to boost cell maturation by giving a mechanical stimulus. Finally, with the aim of creating an effective dynamic cell substrate, we have introduced the design of the first prototype of LCE-based biomimetic contractile unit by optimizing a miniaturization of the mechanical device. The functional properties of the contractile apparatus have been investigated and then modulated to closely reproduce the features of native myocardium. Overall, in this work we have provided an overview of some functional aspects of biomaterials which are considered of key relevance in different biomedical fields to elucidate how recent advances may impact future tissue engineering applications.

Introduction: The development of liver fibrosis is characterised by dramatic changes in the biomechanical composition and mechanical properties of the extracellular matrix (ECM). Increases in matrix stiffness associated with inflammation and fibrosis are implicated in promoting cancer development. Clinical studies have demonstrated a close association between increases in liver stiffness and the incidence of hepatocellular carcinoma (HCC). The effect of changes in matrix stiffness on tissue-resident hepatic progenitor cells (HPC) is unknown. Aberrant HPC proliferation has been implicated in the pathogenesis of HCC. It was hypothesised that changes in the stiffness of the cellular microenvironment are important in regulating the behaviour of liver-resident cell populations and may promote the development of HCC. Aims: i) to determine how changes in the stiffness of the cancer cell niche might regulate proliferation, differentiation and chemotherapeutic resistance in HCC; ii) to determine the relationship between changes in liver stiffness and hepatic progenitor cell (HPC) response in rodent models of chronic liver disease; and iii) to determine whether changes in the stiffness of the HPC niche regulate proliferation and differentiation in these cells. A secondary aim of the thesis was to characterise the pattern of histological changes observed in rodent models of chronic hepatic congestion and whether this might provide insight into the effect of oedema and congestion on the development of liver fibrosis. Methods: Cell culture experiments in HCC (Huh7/ HepG2) and HPC cell lines were performed using a system of ligand-coated polyacrylamide (PA) gel supports of variable stiffness. The stiffness of the PA supports (expressed as shear modulus) was altered across a physiological change (1-12kPa) corresponding to values encountered in normal and fibrotic livers. Thiacetamide and carbon tetrachloride (CCl4) models of liver fibrosis were used to investigate the relationship between increasing liver fibrosis, changes in matrix stiffness and HPC response. The pattern of histological changes in the liver in response to hepatic congestion was assessed in two unrelated murine models of dilated cardiomyopathy; the python and CREB S133A mice. Results: Increases in matrix stiffness, as would be encountered in liver fibrosis, promote HCC cell proliferation. Increasing matrix stiffness is associated with enhanced basal and hepatocyte growth factor-mediated signalling though ERK, PKB/ Akt and STAT3. Stiffness-dependent HCC cell proliferation is modulated by β1-integrin and focal adhesion kinase. Increasing matrix stiffness is associated with a reduction in chemotherapy-induced apoptosis in HCC cells. However, following chemotherapy there was an increase in the frequency of clone-initiating cells for cells maintained in a low stiffness environment. Flow cytometry in HepG2 cells demonstrated that culture in a low stiffness environment was associated with an increase in the frequency of the stem cell markers CD44, CD133 and CXCR-4. This effect was further enhanced in the presence of chemotherapy. There is a close association between HPC numbers and liver stiffness measurements in a rat CCl4 model of chronic liver fibrosis. The major expansion in HPC numbers in this model coincides with a similarly large increase in fibrous tissue deposition. In vitro experiments using PA supports demonstrate that increasing matrix stiffness promotes the proliferation of both primary murine HPCs and an immortalised HPC line (BMOL). Changes in matrix stiffness regulate the expression of hepatocyte and biliary markers in BMOL cells. Histological studies in both the Python and CREB S133A models reveal findings consistent with acute on chronic cardiac hepatopathy (ischaemic hepatitis). Features of chronic passive congestion and centrilobular necrosis are present concurrently and develop rapidly. Bridging fibrosis and cirrhosis are not present. Conclusions: Physiologically-relevant changes in matrix stiffness regulate proliferation, differentiation, chemotherapeutic-resistance and stem cell marker expression in HCC cells. Similarly, increases in matrix stiffness are closely correlated to HPC response in vivo and regulate HPC proliferation and differentiation in vitro.

Background Chronic Obstructive Pulmonary disease (COPD) is an under-diagnosed disease with a prevalence of approximately 10%, highly dependent on age and smoking habits. Comorbidities are common in COPD and of these, cardiovascular diseases (CVD) are the most common. COPD is the fourth leading cause of death globally, and CVD probably contribute to the high mortality. Within CVD, Ischemic Heart Disease (IHD) is the most common. It is highly clinically relevant to identify signs of ischemic heart disease, other cardiac conditions, and risk factors for CVD in COPD. Electrocardiogram (ECG) is a simple but still major diagnostic tool in clinical cardiology, including disturbances in the electric conduction system and ischemia. Due to the under-diagnosis of COPD, there is limited knowledge regarding the prevalence and prognostic impact of ECG abnormalities in COPD. Arterial stiffness is a risk factor for CVD, which has raised an increased interest, however not evaluated in population based studies of COPD. Aim The overall aim was to describe cardiovascular aspects on COPD, with a specific focus on arterial stiffness, prevalence and prognostic impact of ischemic ECG abnormalities and prolonged QT interval, by comparing subjects with and without obstructive lung function impairment in a population-based cohort. Methods The thesis is based on the Obstructive Lung Disease in Northern Sweden (OLIN) COPD study; a population-based longitudinal cohort study. During the years 2002-2004, all participants in clinical examinations from previously recruited large population-based cohorts were invited to re-examination including spirometry and a structured interview. All subjects with obstructive lung function impairment (n=993) were identified, together with 993 age and sex-matched referents without airway obstruction. The study population (n=1986) has been invited to annual examinations since 2005 including spirometry and structured interview. Papers I-III are based on data from 2005 when electrocardiogram (ECG) was recorded in addition to the basic program. All ECGs were Minnesota coded and QT-time was measured. Paper IV is based data from 2010 when non-invasive measurements of arterial stiffness, assessed as pulse wave velocity (PWV), was added to the program. Spirometric data were classified as normal lung function (NLF), restrictive spirometric pattern (RSP) and airway obstruction (COPD). The following spirometric criteria for COPD were used: post-bronchodilator FEV1/VC<0.70 (papers I-IV, in paper III labelled GOLD-COPD) and lower limit of normal, LLN (LLN-COPD) (paper III). Spirometric classification of COPD severity was based on FEV1 % predicted as a continuous variable or according to the Global Initiative for Obstructive Lung Disease (GOLD), divided into GOLD 1-4. Results The prevalence of ischemic heart disease (IHD), both self-reported and assessed as probable and possible ischemic ECG abnormalities (I-ECG) according to the Whitehall criteria, was similar among subjects with NLF and COPD. The prevalence of both self-reported and probable (I-ECG) according to Whitehall increased by GOLD grade.  Among those with COPD, self-reported IHD was associated with disease severity, assessed as FEV1 % predicted also after adjustment for age and sex (paper I). In both COPD and NLF, those with I-ECG had a higher cumulative mortality over 5 years than those without I-ECG (29.6 vs. 10.6%, p<0.001 and 17.1 vs. 6.3 %, p=0.001). When analysed in a multivariate model, the Mortality Risk Ratio (MRR, 95%CI) was increased for subjects with COPD and I-ECG (2.4, 1.5-3.9), and non-significantly so for NLF with I-ECG (1.65, 0.94-2.90), when compared to NLF without I-ECG.  When analyzed separately among subjects with COPD, the increased risk for death associated with I-ECG persisted independent of age, sex, BMI-class, smoking habits and disease severity assessed as FEV1 % predicted (1.89, 1.20-2.99). The proportion without reported IHD was high among those with I-ECG; 72.4% in NLF and 67.3% in COPD. The pattern was similar also among them; I-ECG was associated with an increased risk for death in COPD and non-significantly so in NLF (paper II). Mean corrected QT-time (QTc) and prevalence of QTc prolongation was higher in RSP than NLF but similar in NLF and GOLD-COPD. The prevalence of borderline as well as prolonged QTc increased by GOLD grade (test for trend p=0.012 for both groups). Of those with GOLD-COPD, 52% fulfilled the LLN-criterion (LLN-COPD). When comparing LLN-COPD and NLF, the pattern was similar as when comparing NLF and GOLD-COPD. The cumulative mortality over 5 years was higher among subjects with borderline and prolonged QTc than those with normal QTc in subjects with GOLD-COPD and LLN-COPD but not in NLF and RSP (paper III). Arterial stiffness, assessed as PWV, was higher in GOLD 3-4 compared to non-COPD (10.52 vs. 9.13 m/s, p=0.042). Reported CVD and age >60 were both associated with significantly higher PWV in COPD as well as in non-COPD. In a multivariate model, GOLD 3-4 remained associated with higher PWV when compared with non-COPD, also when adjusted for sex, age group, smoking habits, blood pressure, reported CVD and pulse rate (paper IV). Conclusion In this population-based study, the prevalence of ischemic ECG abnormalities was similar among subjects with normal lung function and COPD, but increased by disease severity among subjects with COPD. Ischemic ECG abnormalities were associated with an increased mortality among subjects with COPD, independent of common confounders and disease severity, also among those without known heart disease. Whilst the prevalence of QTc prolongation was similar in NLF, COPD and LLN-COPD, it was associated with an increased mortality only in the COPD-groups. ECG is a simple non-invasive method and seems to identify findings of prognostic importance among subjects with COPD. Central arterial stiffness, a known risk factor for cardiovascular disease, was increased among subjects with severe and very severe COPD when compared to subjects without COPD independent of common confounders.

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.

QC 20161115

Background: Aortic stiffness as measured by pulse wave velocity (PWV) is a predictor of cardiovascular disease and other outcomes in different diseased and healthy populations, independent of traditional risk factors. The relationships between PWV measurement, global functional outcome and injury to the brain, kidney, and heart have never been examined in cardiac surgery patients. Objective: The objective of this project was to assess the relationship between aortic stiffness and health related quality of life (QoL), cognitive function, acute kidney injury (AKI), and cardiac function in patients undergoing aortic valve replacement (AVR). Methods: Aortic PWV, QoL, cognitive function, left ventricular (LV) function and NYHA class were assessed pre- and post-operatively (409 ± 159 days). The brain injury biomarker, N-methyl-D-aspartate receptor antibody (NR2Ab), was measured pre-operatively only. The biomarker of myocardial strain, B-type natriuretic peptide (BNP), and the novel AKI biomarker, neutrophil gelatinase-associated lipocalin (NGAL), were measured pre-operatively, and at 3 h and 18-24 h post-CPB. Results: Fifty-six patients (16 females; mean age, 71 ± 8.4 years) were included in this study, of which 50 (89%) patients attended the follow-up visit. No relationship was found between the degree of aortic stenosis (AS) and PWV, and AVR had no effect on aortic stiffness post-operatively. QoL and NYHA class significantly improved, while cognitive function did not deteriorate after AVR. High PWV is independently related to poorer QoL, cognitive function levels and NYHA class both pre- and post-operatively. PWV was not related to LV function, BNP or NGAL levels, but it was independently related to the level of NR2Ab. PWV did not correlate with AKI which was developed in 30% of the cases. Early post-operative plasma level of NGAL is the earliest predictive marker of post-operative AKI and the need for early medical renal intervention. Pre-operative BNP level was significantly and negatively correlated with pre-operative LV function, AS (valve area), and NYHA class in the post-operative follow-up period. Conclusion: In AVR patients, PWV is independently related to global functional status, cognitive function and brain injury biomarkers, but is not related to AKI or myocardial strain.

L’élastographie ultrasonore est une technique qui a fait ses preuves en clinique depuis près de 10 ans pour explorer la dureté des organes statiques superficiels comme le foie le sein. Son application à l’étude des caractéristiques mécaniques du cœur est très récente et n’a fait l’objet que de quelques preuves de concept expérimentales chez l’animal et chez l’Homme. Dans ce travail, nous avons évalué in vitro, sur un modèle animal et chez l'homme atteint de sténose aortique, l'imagerie Shear Wave Elastography dans une version adaptée au cœur à partir de séquences cliniques conçues pour des organes statiques. Nous avons montré sur fantôme que les mesures réalisées à l’aide des séquences cardiaque sur sonde linéaires étaient concordantes avec les séquences de référence, alors que les mesures avec la sonde sectorielle n'étaient interprétables qu'entre 4 et 10 cm, et présentaient un champ de mesure homogène. Dans le modèle animal, nous avons montré que la rigidité systolique était affectée par les conditions de charge et corrélée à la contractilité, alors que la rigidité diastolique était indépendante des conditions de charge, de la contractilité et de la fréquence cardiaque avec une bonne concordance intra et inter animale. Chez l'homme, nous avons confirmé la nature dynamique de la dureté myocardique avec un rapport systole/diastole de 3,5, montré que la rigidité diastolique du myocarde était significativement plus élevée en cas de sténose aortique et significativement corrélée au remodelage du ventricule gauche, à la sévérité de l'obstruction aortique et à la précharge ventriculaire. Ces résultats prometteurs montrent le bénéfice clinique potentiel de cette modalité si elle était largement mise en œuvre sur des machines commerciales
Ultrasonic elastography is a validated technique used for almost 10 years to evaluate the stiffness of superficial static organs such as the liver and the breast. Its application to the study of the mechanical characteristics of the heart is very recent, and has been the subject of only a few experimental proof of concept studies in animals and humans. In this work, we evaluated Shear Wave Elastography imaging in a version adapted to the heart from clinical sequences designed for static organs, successively in vitro, in an animal model and in humans with aortic stenosis,. In the phantom study, we showed that measurements with cardiac sequences and linear probes were consistent with reference sequences, whereas measurements with the sectorial probe were only interpretable between 4 and 10 cm, and presented a homogeneous measurement field. In the animal model, we showed that systolic stiffness was affected by loading conditions and correlated with contractility, while diastolic stiffness was independent of loading conditions, contractility short ischemia and heart rate, with good intra- and inter-animal agreement. In humans, we confirmed the dynamic nature of myocardial stiffness with a systole/diastole ratio of 3.5, showed that diastolic myocardial stiffness was significantly higher in aortic stenosis and significantly correlated with left ventricular remodeling, severity of aortic obstruction and ventricular preload. These promising results demonstrate the potential clinical benefit of this modality if widely implemented on commercial systems

Preeclampsia is one of the leading causes of maternal and fetal mortality and morbidity. Furthermore, women who have had preeclampsia have an increased risk of cardiovascular events over the next 10-15 years. Indeed, preeclampsia is associated with a four-fold increase in the risk of hypertension and double the risk of fatal and non fatal ischaemic heart disease and stroke. In addition, offspring born to preeclampsia are more likely to have higher blood pressure from childhood and stroke in later life. The risk to mother and offspring is greatest when preeclampsia is diagnosed at an earlier gestation, suggesting a more severe form of preeclampsia. As the long term cardiovascular risk to both mother and child is known from delivery, the main interest of my research was to identify key phenotypic variations in mothers and children during the years between the episode of preeclampsia and emergence of established cardiovascular disease, which might explain the link between the two conditions. This information could then be used to devise ways to identify subjects at greatest risk of later cardiovascular disease and to establish intermediate endpoints for future preventative interventions. Therefore, in a case control study, women diagnosed with preeclampsia between 1998 and 2003 and their offspring were recruited and underwent comprehensive cardiovascular and metabolic phenotyping. Furthermore, young adults born preterm to hypertensive pregnancy were also investigated in their twenties. The research demonstrates that early-onset preeclampsia, diagnosed before 34 weeks gestation, is associated with blood pressure patterns in mothers 6-13 years after pregnancy that are distinct from those seen following later-onset disease. Furthermore, there is evidence of distinct differences in cardiac, vascular and metabolic profiles in these individuals with women having evidence of increased arterial stiffness, changes in cardiac function and reduced capillary density. Preterm offspring of hypertensive pregnancies similarly have higher blood pressure than seen in those born following late-onset disease and, in young adult life, have reduced endothelial function and changes in cardiac size proportional to this dysfunction. This research demonstrates adverse cardiac and vascular remodelling after preeclampsia in mothers and offspring that are evident before the development of clinical cardiovascular disease. The identified differences in cardiac and vascular function may be useful as surrogate endpoints in future preventive trials.

Background: Thoracic aortic aneurysms and dissections (TAAD) have a genetic component with an estimated 20-25% of the patients having a positive family history. An aneurysm often precedes a dissection. Acute aortic dissections are associated with high mortality and morbidity, even when operated on. Complications due to prophylactic surgery are considerably fewer. Therefore, patients at risk for dissection should be identified, followed-up and evaluated for prophylactic intervention. Aims: 1. To establish reference values for ascending (AoA) and descending aortic (AoD) diameters measured by computed tomography. 2. To study the effectiveness of phenotypic cascade screening in families with an inherited form of thoracic aortic aneurysms and dissections (FTAAD) and to address questions that arise when screening for a genetic disorder is applied. 3. To study the agreement of aortic diameters obtained by TTE and MRI and to study aortic stiffness in individuals from families with FTAAD. 4. To perform exome sequencing in order to identify pathogenic sequence variants causing FTAAD, to characterize the phenotype, and to compare thoracic aortic diameter and stiffness in mutation carriers and non-carriers. Results: Paper I: The diameter of the thoracic aorta increased by 0.17 mm (0.12 – 0.20 mm) per year. The mean sex-related difference in diameter was 1.99 mm (1.28 – 2.60 mm) with men having larger aortas than women. The mean difference in aortic diameter per unit BMI was 0.27 mm (0.14 – 0.44 mm). Upper normal limits for the AoA can be calculated by the formula D (mm)=31+0.16*age and for the AoD by D (mm)=21+0.16*age. Paper II: Of 106 individuals from families with FTAAD but without known thoracic aortic disease, 19 individuals (18%) were identified to have a dilated AoA. The expected number of individuals in this group with an autosomal dominant disease would have been 40 (p<0.0001). In first-degree relatives younger than 40, we found only one individual with a dilated aorta although the expected number of individuals with disease causing mutation would have been 10. Paper III: Of 116 individuals investigated, 21 were identified with thoracic aortic dilatation and 95 individuals with normal thoracic aortic diameter. Aortic stiffness increased with age and diameter. The individuals with aortic dilatation were older than those without (49 vs. 37 years, p=0.001) and showed lower aortic elastic properties. The diameters measured by TTE and MRI correlated strongly (r2=0.93). The mean difference in diameters between the two methods was 0.72 mm (95% CI 0.41-1.02) with TTE giving larger diameters than MRI. Paper IV: From exome sequencing and segregation analysis, a 2-bp deletion in the MYLK gene (c.3272_3273del) was identified to cause FTAAD. The age and the aortic diameter at dissection or rupture varied in the family members. We did not find any differences in aortic diameter, aortic stiffness, or pulse wave velocity between carriers and non-carriers. Conclusions: Thoracic aortic diameter increases with age, and sex and body size are also associated with the diameter. In FTAAD, screening identifies family members with a previously unknown aortic dilatation. However, a normal aortic diameter does not exclude an individual from being a carrier of FTAAD. TTE can be used in follow-up for the ascending aorta. Individuals identified to have a dilated thoracic aorta have increased aortic stiffness compared to individuals with normal thoracic aortic diameter. The MYLK mutation (c.3272_3273del) causes thoracic aortic dissections with variable clinical expression. No differences in aortic stiffness were identified between MYLK mutation carriers and non-carriers.

Advancements in clinical care have led to a growing cohort of preterm-born individuals now entering adulthood. Before birth, such adults were often exposed to a suboptimal intrauterine environment, and after delivery, key developmental stages that would normally occur in utero during the third trimester had to take place under ex utero physiological conditions. Through detailed cardiovascular phenotyping, this thesis investigates the cardiovascular changes in preterm-born young adults, utilising a cohort of individuals with data collection since recruitment at birth. The detailed perinatal information was first used to design nested case-control studies to investigate the effects of early lipid and glucocorticoid exposure on long-term cardiovascular physiology in individuals born preterm. It was demonstrated that intravenous lipid administration leads to an artificial elevation of total cholesterol levels in immediate postnatal life, which is associated with long-term changes in aortic and left ventricular function proportional to the degree of cholesterol elevation. Additionally, exposure to antenatal glucocorticoids relates to a regional increase in aortic arch stiffness in young adulthood, as well as changes in glucose metabolism. It was then shown that young adults born preterm have increased left ventricular mass, out of proportion to blood pressure, and a unique three-dimensional left ventricular geometry, with reduced systolic and diastolic function compared to term-born controls. Similarly, they also show distinct differences in the right ventricle, with increased right ventricular mass and a proportion having clinically impaired right ventricular systolic function. Finally, it was demonstrated that preterm-born individuals have increased circulating levels of antiangiogenic factors in young adulthood, which relate to capillary rarefaction and blood pressure elevation. These findings are of considerable public health relevance given that nearly 10% of births are now preterm. Understanding whether modification of these variations in cardiovascular structure and function prevent the development of cardiovascular disease in this growing subgroup of the population will be of future interest.

L’objectif de cette thèse est d'analyser en échocardiographie le remodelage et la fonction cardiaque après correction optimale d’un obstacle congénital du cœur gauche et d’identifier de potentiels marqueurs de risque de survenue de fibrillation atriale. Le premier axe de ce travail est une étude prospective multicentrique qui présente le profil évolutif des arythmies atriales chez les adultes porteurs d’une cardiopathie congénitale. Cette étude démontre l’importance de la fibrillation atriale qui devient l’arythmie prédominante après l’âge de 50 ans chez ces patients. Le deuxième axe de travail s’intéresse à la rigidité atriale, un indice échocardiographique corrélé à la présence de fibrose et à la survenue de fibrillation atriale. Nous avons montré que la rigidité atriale est anormale malgré la correction optimale d’un obstacle congénital du cœur gauche, en particulier chez les patients opérés d’une coarctation aortique. Les troisième et quatrième axe de recherche ont exploré spécifiquement le remodelage et la fonction cardiaque après cure de coarctation. Dans la troisième étude, l’analyse en 2D strain a permis d’identifier une forte prévalence de dysfonction atriale chez des adultes et adolescents opérés d’une coarctation aortique. La fonction atriale est influencée par l’anatomie de l’arche aortique ; une relation entre la fonction atriale et la survenue d’évènements cardiovasculaires a été trouvée. Enfin, dans le dernier travail, l’analyse du cœur droit en 2D strain a permis de révéler des anomalies de la fonction ventriculaire droite après cure de coarctation. Nos résultats illustrent l’apport potentiel des nouvelles techniques d’imagerie comme le 2D strain pour identifier des patients à risque de développer une fibrillation atriale dont la prévention est un des enjeux majeurs de la cardiologie congénitale adulte
The objective of this thesis is to analyze myocardial mechanics and cardiac remodeling and function, using transthoracic echocardiography, after optimal correction of a congenital obstruction of the left ventricle and to identify potential risk markers for the occurrence of atrial fibrillation. The first focus of this work is a prospective multicenter study presenting the evolutionary pattern of atrial arrhythmias in adults with congenital heart disease. This study demonstrates the prominence of atrial fibrillation, which becomes the predominant atrial arrhythmia after the age of 50 in these patients. The second area of study focuses on left atrial stiffness, a recent echocardiographic index well correlated with the presence of atrial fibrosis and occurrence of atrial fibrillation. We demonstrate that left atrial stiffness may be abnormal despite optimal correction of a congenital left heart obstruction, especially in patients experiencing aortic coarctation and in overweight patients. The third and fourth lines of research specifically explore remodeling and cardiac function in patients whose aortic coarctation has been repaired. In the third area of research, we use two-dimensional strain analysis to detect a high prevalence of left atrial dysfunction in adults and adolescents after aortic coarctation repair. Left atrial dysfunction is influenced by the anatomy of the aortic arch; a potential relationship with cardiovascular events and left atrial function is identified. Finally, in the last area of research, we identify anomalies of the right ventricular function after coarctation repair. Our results illustrate the potential contribution of new imaging techniques such as two-dimensional strain to identify patients at risk of developing atrial fibrillation, the prevention of which is one of the current challenges in adult congenital cardiology

Hemodynamic effects of insulin resistance (IR) are thought to be largely dependent on its relationship with body mass index (BMI) and blood pressure (BP) levels. The first part of the present thesis was aimed at exploring whether IR is associated with hemodynamic indices of cardiovascular function in a large sample of non-diabetic individuals from the general population (n=731) and if so, to explore if such relationship is continuous across different categories of BMI (lean, overweight and obese), and BP (normal BP, high-normal BP and hypertension). IR was assessed with the homeostasis model assessment of IR (HOMA-IR). Based on a value of HOMA-IR of 2.09 (75th percentile of distribution curve), subjects were classified as insulin-sensitive (IS, HOMA<2.09) or insulin-resistant (IR, HOMA≥2.09). Synchronized beat-to-beat recordings of stroke volume (impedance cardiography) and R-R interval (ECG), along with repeated BP measurements were performed over 5 minutes. Stroke index (SI), cardiac index (CI), systemic vascular resistance index (SVRI), left cardiac work index (LCWI), pre-ejection period (PEP) and left ventricular ejection time (LVET) were computed and averaged. In analysis of co-variance allowing for confounders, IR subjects showed significantly higher BP levels and SVRI, and reduced R-R interval, SI, CI, LCWI, PEP and LVET. These differences remained significant when analyses were performed within each BMI and BP category. Overall, these results indicate that effects of IR on hemodynamic indices of cardiovascular function are continuous across different BMI and BP categories, reinforcing the importance of IR in the pathogenesis of cardiovascular alterations beyond its association with obesity and hypertension. The finding of a significant association between IR and hemodynamic alterations even in lean and normotensive subjects was the rationale to explore potential mechanisms for these alterations in this selected group of subjects. Specific objectives of this second part of the thesis were: 1) To explore the relationship between insulin resistance and systemic hemodynamics, cardiac baroreflex sensitivity and indices of autonomic CV modulation. 2) To explore the relationship of insulin resistance with 24h heart rate, average blood pressure levels and blood pressure variability over the 24h; and 3) To explore the relationship of insulin resistance with central blood pressure levels and with measures of large artery stiffness and wave reflections. The study population for these analyses was constituted by subjects who were below the 30th percentile of diastolic blood pressure (DBP) distribution curve (DBP ≤72 mmHg) and who had no elevation in systolic BP levels. In addition, subjects were excluded in case of diabetes mellitus (fasting blood glucose ≥126 mg/dL or use of medications for previously diagnosed type 2 diabetes) obesity (BMI≥30) or taking medications with effects on BP. A total of 90 subjects fulfilling inclusion criteria were considered for the present analysis and underwent further assessments. Insulin resistance was assessed with HOMA-index and subjects classified into IR tertiles, based on the distribution of HOMA-index values. 24h Ambulatory BP monitoring was performed. Mean SBP and DBP were averaged for the day, night and 24h, and the respective day-to-night dipping was calculated. BPV was assessed for SBP and DBP as 24h standard deviation (SD), weighted 24h SD (wSD), daytime and night-time SD. Recordings of pulse waveform were obtained by means of a previously validated oscillometric device for ambulatory BP monitoring with in-built transfer-function like method. Aortic pulse wave velocity (PWV, m/s) and other measures derived from pulse wave analysis such as augmentation index (AIx, %), central SBP (cSBP), central DBP (cDBP) and central pulse pressure (cPP) were computed. Peripheral SBP and DBP, and heart rate (HR) were recorded and pulse pressure (PP) calculated as the difference between SBP and DBP. Non-invasive assessment of beat-to-beat BP, R-R interval (ECG) and stroke volume (by means of impedance cardiography) were performed during 10 min in supine position and specific hemodynamic indices associated with their measurement were computed and averaged: RRI (msec), heart rate (HR, bpm), stroke volume index (SI, mL/beat/m2), cardiac index (CI, L/min/m2), SBP (mmHg) and DBP (mmHg), systemic vascular resistance index (SVRI, dyn/sec/cm-5/m2), left cardiac work index (LCWI, Kg/m/m2), pre-ejection period (PEP, msec), left ventricular ejection time (LVET, msec) and PEP/LVET ratio were calculated. Cardiac autonomic modulation was assessed by computer analysis of 10 min beat-to-beat BP and ECG recordings in resting supine position. Cardiac baroreflex sensitivity (BRS) was estimated by sequence method. Total variance, low-frequency (LF) and high-frequency (HF) spectral components of HR variability (HRV) were assessed by autoregressive analysis. LF/HF ratio was calculated. After multiple regression analysis, adjusting for common confounders such as age, sex, HR and BMI, increasing values of HOMA-IR were associated with reduced RRI, SI, CI, and with increased SVRI, SBP and DBP. IR was also associated with reduced BRS (up, down, and total slopes), decreased parasympathetic indices of autonomic CV modulation (SDRRI, HF-power, total power) and a predominance of sympathetic component of HRV (increased LF/HF ratio). Increasing values of HOMA-IR were also associated with increased HR and average SBP levels (during day, night and 24-h period), with augmented BP variability (Day SBP SD, and SBP wSD) and with a reduced dipping of HR. Finally, insulin resistance was shown to be associated with increasing values of aortic PWV, and with higher central and peripheral SBP and DBP levels. Overall, these results support significant associations between insulin resistance and changes in hemodynamic and autonomic indices of cardiovascular function, even after accounting for common confounders. These findings suggest that in normotensive healthy adults, increases in insulin resistance may promote alterations in autonomic cardiovascular modulation, in systemic hemodynamics and in arterial stiffness, all of which are known contributors to the pathogenesis of hypertension.

A hipertensão arterial sistêmica (HAS) pós-transplante é frequente e está associada com aumento da morbimortalidade cardiovascular e subsequente disfunção do enxerto, sendo relatada como consequência ao uso de imunossupressores, especialmente os inibidores da calcineurina. Este estudo pretende avaliar o impacto da hipertensão arterial sobre a rigidez arterial calculada utilizando o índice ambulatorial de rigidez arterial (IARA) como desfecho substituto obtido pela monitorização ambulatorial da pressão arterial (MAPA) em pacientes transplantados de coração. Trata-se de um estudo prospectivo, observacional, analítico, com grupo controle, realizado no Hospital de Messejana Dr. Carlos Alberto Studart Gomes, hospital público do estado do Ceará, especializado em doenças cardiopulmonares e de referência em transplante de coração. Foram selecionados pacientes adultos transplantados do coração, os quais passaram por exames clínicos e complementares, e um grupo controle com pacientes não transplantados hipertensos. Todos foram submetidos a MAPA e obtenção do IARA com o objetivo de estimar o risco de rigidez arterial. Foram realizados testes estatísticos de significância e regressão logística para controle de confundimento. A média de idade dos transplantados foi de 55 anos, contra 48 dos não transplantados. A hipertensão prévia foi mais frequente em não transplantados, mas diabetes e doença arterial coronariana foram mais frequentes em transplantados. A média diastólica dos transplantados (82) é significativamente maior que a dos não transplantados (74) e o descenso sistólico é praticamente inexistente em pacientes transplantados (-0,18) que no grupo-controle (9,45). A condição de transplantado do paciente não é determinante de rigidez arterial, mas a hipertensão arterial sistólica na primeira avaliação, a média sistólica em 24h, a média diastólica em 24h, o descenso sistólico, o descenso diastólico e o IARA (parâmetros da MAPA) o são. Este estudo encontrou que num grupo de transplantados de coração adultos, a hipertensão arterial sistêmica está independentemente associada com a rigidez arterial estimada pelo IARA, que é um novo método, não invasivo, de fácil execução e de baixo custo. A evidência demonstrada por este estudo pode auxiliar no direcionamento de tratamento dos pacientes transplantados, contribuindo com melhoria do prognóstico
Hypertension post cardiac transplant is frequent and is associated with increased cardiovascular morbidity and mortality and graft dysfunction, being reported because of the use of immunosuppressant, especially the calcineurin inhibitors. This study aims to evaluate the impact of hypertension on the arterial stiffness calculated using the IARA as surrogate outcome obtained by the Home Blood Pressure Monitoring in heart transplanted patients. This is an observational study, analytical, with the control group, in Heart and Lung Messejana´s Hospital, a public institution in the State of Ceará, which is specialized in cardiopulmonary diseases and especially in heart transplant, with adult patients cardiac transplanted, which underwent clinical and complementary exams, from which were obtained the IARA. Statistical significance tests and logistic regression to control for confounding were performed. The average age of transplanted was 55 years, against 48 of the non-transplanted. Hypertension was more frequent in prior not transplanted, but diabetes and coronary artery disease were more frequent in transplanted. The average diastolic of transplanted (82) is significantly higher than the non-transplanted (74) and decrease systolic is virtually nonexistent in transplant patients (-0.18) than in the control group (9.45). The condition of the transplanted patient is not determinant of arterial stiffness (p = 0.105), but are the systolic hypertension in the first evaluation, the average systolic, diastolic average in 12:0 am 12:0 am, systolic, diastolic descent and the IARA (parameters of the HBPM). This study showed that in a group of adult cardiac transplanted, hypertension is independently associated with arterial stiffness estimated by IARA, which is a new method, non-invasive, easy to perform and inexpensive. The evidence demonstrated by this study may assist in treatment of transplanted patients, contributing to improving the prognosis

O transplante cardíaco permanece sendo o procedimento de escolha para a insuficiência cardíaca refratária, apresentando resultados favoráveis em termos da sintomatologia, qualidade de vida e sobrevida desses pacientes. A hipertensão arterial sistêmica aparece como a comorbidade de maior incidência neste grupo de pacientes, chegando a 95% após cinco anos. O efeito do exercício físico sobre a dinâmica do comportamento tensional na monitorização da pressão arterial ambulatorial durante 24 horas (MAPA-24h) e da rigidez arterial não tem sido estudado neste grupo de pacientes. Nós avaliamos os efeitos da atividade física aeróbia sobre a dinâmica do comportamento tensional na MAPA-24h, rigidez arterial e as variáveis cardiovasculares em indivíduos após um ano de transplante cardíaco. Trinta e nove pacientes de ambos os sexos, randomizados para grupo treino (GT) (n = 29; 45 ± 13 anos) ou grupo controle (GC) (n = 9; 51 ± 11 anos) realizaram, antes e após o período de 12 semanas de seguimento, exames de MAPA-24h, velocidade de onda de pulso carótido-femoral (VOP) e teste de esforço cardiopulmonar, com coletas de amostras sangüíneas para dosagem de norepinefrina (Nor) (repouso e pico). Treinamento físico aeróbio foi realizado três vezes por semana, sendo duas supervisionadas e uma não supervisionada, durante 40 minutos inicialmente com a frequência cardíaca monitorada em 80% do ponto de compensação respiratória. O GT apresentou redução significativa da pressão arterial sistólica nos períodos da média das 24 horas (de 120 ± 11 para 116 ± 14mmHg, p<0,05) e vigília (de 123 ± 11 para 118 ± 13mmHg, p<0,05). A pressão arterial diastólica apresentou redução significativa para os três períodos sendo na média das 24 horas (de 81 ± 9 para 74 ± 9mmHg, p< 0,001), vigília (de 83 ± 9 para 75 ± 10mmHg, p<0,001) e noturno ( de 77 ± 10 para 71 ± 10mmHg, p<0,001). A VOP não apresentou redução significativa após o período de seguimento para ambos os grupos; GT (de 10,0 ± 1,9 para 9,7 ±1,9m/s, p = ns) e GC (de 10,3 ± 2,2 para 10,4 ± 2,8m/s, p = ns), porém os níveis da Nor tiveram aumento significativo no pico do exercício no grupo GT (de 2386 ± 1274 para 3292 ± 1410 pg/ml p<0,01) e também em relação ao grupo GC pós seguimento (3292 ± 1419 versus 2178 ± 659 pg/ml, p<0,05). O treinamento físico aeróbio reduziu a pressão arterial sistólica/diastólica em 4,7/7,5 mmHg durante a vigília e em 3,5/5,8 mmHg durante o sono após TX, além de melhorar o condicionamento cardiorrespiratório com aumento do VO2pico, FCmáx e do tempo de exercício.
Cardiac transplantation remains the procedure of choice for refractory heart failure, with favorable results in terms of symptoms, quality of life and patient survival. Hypertension appears as a higher incidence of comorbidity in this group of patients, reaching 95% after five years. However, the effect of exercise training in the behavior of 24-hour ambulatory blood pressure monitoring (ABPM) and arterial stiffness has not been studied in this group of patients. We assessment the effects of aerobic physical activity in the behavior of ABPM, arterial stiffness and cardiovascular variables in patients being heart transplanted for a year or more. Thirty-nine patients of both genders were evaluated, then randomized to either training group (TG) (n = 29, 45 ± 13 years) or control group (CG) (n = 9, 51 ± 11 years) and reevaluated after 12 weeks of follow-up. Pre and post evaluations combined examinations of ABPM, carotidfemoral pulse wave velocity (PWV) and graded exercise test, with collections of blood samples for measurement of norepinephrine (Nor) (rest and peak). Aerobic exercise was performed in the TG three times-a-week, two supervised and one unsupervised for 40 minutes initially at an intensity of 80% of heart rate achieved at the respiratory compensation point. The TG showed a significant reduction in systolic blood pressure during average of 24 hours (from 120 ± 11 to 116 ± 14mmHg, p < 0.05) and diurnal cycle (from 123 ± 11 to 118 ± 13mmHg, p<0.05). Diastolic blood pressure decreased significantly for the three periods, the average of 24 hours (from 81 ± 9 to 74 ± 9mmHg, p<0.001), diurnal cycle (from 83 ± 9 to 75 ± 10mmHg, p < 0.001) and nighttime (from 77 ± 10 to 71 ± 10mmHg, p < 0.001). The PWV showed no significant reduction after the followup period for both groups; TG ( from 10.0 ± 1.9 to 9.7 ± 1.9m/s, p = ns) and CG (from10.3 ± 2.2 to 10.4 ± 2.8m/s, p = ns) and the levels of the Nor had a significantly higher peak exercise in TG (from 2386 ± 1274 to 3292 ± 1410 pg/ml p <0.01) and also in relation to the control group after follow-up (3292 ± 1419 versus 2178 ± 659 pg / ml, p <0.05). The exercise training reduced both systolic and diastolic blood pressure in 4.7 and in 7.5 mmHg during daytime, respectively. Reduction also happened during nighttime in 3.5 and in 5.8 mmHg for these variables, respectively. Exercise training improved VO2peak, HRmax and time of exercise (cardiorespiratory fitness) after follow-up, as well.

Introdução: A apneia obstrutiva do sono (AOS) é uma condição clínica comum associada com o aumento do risco cardiovascular. No entanto, a maioria dos estudos envolvendo AOS e desfechos cardiovasculares recrutaram de forma preponderante os homens. Em pacientes hipertensos, a AOS pode contribuir para a lesão de órgãos-alvo e alterações no descenso noturno em homens. O impacto da AOS nas mulheres hipertensas é pouco estudado. O objetivo deste estudo é estudar o impacto da AOS na rigidez arterial da aorta (avaliada pela velocidade da onda de pulso, VOP, carótida-femoral), disfunção diastólica e alterações do descenso noturno da pressão arterial em ambos os gêneros. Fazemos a hipótese de que a AOS está associada com alterações na rigidez arterial, disfunção diastólica e comportamento da pressão arterial independente do gênero. Métodos: Recrutamos de forma consecutiva pacientes hipertensos estágio 2 do ambulatório de Hipertensão do Instituto do Coração. Padronizamos a medicação anti-hipertensiva (hidroclorotiazida 25mg ao dia e enalapril 20mg 2x ao dia ou losartan 50mg 2x ao dia em caso de intolerância ao enalapril) por 1 mês. A adesão do tratamento aconteceu por meio da contagem de pílulas. Foram realizadas avaliações da monitorização ambulatorial da pressão arterial (MAPA), VOP, ecocardiograma transtorácico, exames laboratoriais e a Polissonografia Noturna. A AOS foi diagnosticada por um índice de apneia e hipopneia >= 15 eventos por hora de sono. Resultados: Foram inicialmente recrutados 125 participantes e após as exclusões, avaliamos 95 pacientes hipertensos (56% mulheres). A frequência da AOS foi de 66,7% em homens e 45,3% em mulheres (p=0,02). Em relação às mulheres sem AOS, mulheres com AOS eram mais velhas, tinham maior índice de massa corpórea e apresentaram maiores circunferências cervical e abdominal. Os homens com e sem a AOS foram semelhantes em várias características, exceto por uma circunferência abdominal maior no grupo com AOS. Comparado aos pacientes sem AOS, a VOP foi estatisticamente maior nos homens portadores de AOS (11,1±2,2 vs. 12,7±2,4m/s, respectivamente; p=0,04), assim como nas mulheres (11,8±2,4 vs. 13,2±2,2m/s, respectivamente; p=0,03). Em relação à disfunção diastólica, apenas as mulheres com AOS mostraram maior porcentagem dessa alteração ecocardiográfica (46,1 vs. 81,8%, respectivamente; p=0,007). Foi visto nos resultados da MAPA, que homens com AOS apresentaram menor frequência do descenso noturno sistólico (46,4 vs. 14,3%, respectivamente; p=0,04) e as mulheres, uma tendência (65,2 vs. 41,4%; p=0,07). O resultado da regressão linear mostrou que a presença de AOS promove aumento independente nos valores da VOP. O resultado da regressão logística evidenciou que a presença da AOS não foi associada com a disfunção diastólica, mas foi com a ausência do descenso noturno do componente sistólico da pressão arterial. Conclusões: Em pacientes hipertensos, a presença da AOS foi associada com um aumento na rigidez arterial independente do sexo, assim como a ausência do descenso noturno do componente sistólico da pressão arterial. Estes dados sugerem que mulheres hipertensas também estão expostas às consequências vasculares da AOS
Introduction: Obstructive sleep apnea (OSA) is a common condition associated with increased cardiovascular risk. However, most of studies that addressed OSA and its cardiovascular consequences enrolled mainly men. In hypertensive patients, OSA may contribute to increased target organ damage and alterations in the blood pressure dipping in males. However, the impact of OSA in hypertensive females is not well established. In this study, we compared the impact of OSA on arterial stiffness of the aorta (evaluated by carotid-femoral pulse wave velocity, PWV), as well as diastolic dysfunction and blood pressure dipping in men and women with hypertension. We made the hypothesis that OSA is associated with higher arterial stiffness, higher frequency of diastolic dysfunction and impaired blood pressure behavior regardless of gender. Methods: We recruited consecutives stage 2 hypertensive patients from the outpatient clinic at the Heart Institute. We performed a 30-day standardized anti-hypertensive treatment with hydrochlorothiazide 25mg per day plus enalapril 20mg BID or losartan 50mg BID (if enalapril intolerance). Adherence to treatment was confirmed through pill counting. After that, all volunteers were submitted to clinical evaluation, carotid-femoral PWV, 24-hour ambulatory blood pressure monitoring, transthoracic echocardiogram, and polysomnography. OSA was defined by an apnea-hypopnea index >= 15 events per hour. Results: We initially recruited 125 participants and after exclusions ninety-five patients were studied (56% women). OSA was present in 52 patients (men: 66.7%; women: 45.3%; p=0.02). In comparison to women without OSA, women with OSA were older, had higher body mass index and higher neck and abdominal circumferences. In men, there were no differences between OSA and no-OSA groups, except for higher values of abdominal circumference in OSA patients. Compared to no-OSA patients, PWV values were higher in the OSA group among both males (11.1±2.2 vs. 12.7±2.4m/s, respectively; p=0.04) and females (11.8±2.4 vs. 13.2±2.2m/s, respectively; p=0.03). The impact of OSA on diastolic dysfunction was significant only in females (46.1 vs. 81.8%, respectively; p=0.007). Regarding ambulatory blood pressure monitoring data, the frequency of systolic blood pressure dipping was significantly lower in men with OSA (46.4 vs. 14.3%, respectively; p=0.04) and marginal but non-significant in women (65.2 vs. 41.4%; p=0.07). Linear regression analysis showed that the presence of OSA was independently associated with higher PWV. In the logistic regression analysis, OSA was not associated with diastolic dysfunction but independently associated with nondipping systolic blood pressure. Conclusion: In patients with hypertension, OSA has significant associated with higher arterial stiffness and nondipping systolic blood pressure regardless of gender. These data suggest that hypertensive women are also exposed to the vascular and hemodynamic consequences of OSA

A obesidade é uma doença crônica com complicações para a qual se busca o tratamento e a prevenção. A gordura visceral é um órgão endócrino de armazenamento hormonal e produtor de adipocinas inflamatórias, tornando o obeso portador de inflamação crônica, que por sua vez é uma das características da aterogênese e do envelhecimento. Os níveis aumentados de interleucina-6 e fator de necrose tumoral-alfa, citocinas multifuncionais, estão associados à morbi-mortalidade em idosos e à patogênese da aterosclerose. Nos dias atuais, a alimentação mundial é caracterizada pelo aumento do consumo de gordura saturada e gorduras trans, bem como pela redução do consumo de ácidos graxos ômega-3. O desequilíbrio na relação ômega-6/ômega-3 propicia um ambiente de inflamação crônica, sendo o estímulo inicial para doenças degenerativas. A substituição de gorduras saturadas por ácidos graxos poliinsaturados, de ácido alfa- linolênico (ALA) - ômega-3, e de ácido graxo monoinsaturado (ácido oléico - ômega- 9), parece estar associada à redução do risco de doença cardiovascular. Entre duas fontes de ácido eicosapentaenóico e ácido docosahexaenóico, os ácidos graxos ômega-3 provenientes de peixes e o ALA das fontes vegetais, este último é mais acessível financeiramente e amplamente disponível no mundo todo. Este estudo foi desenhado para avaliar comparativamente o efeito do aumento do consumo de ALA proveniente de fontes vegetais sobre os indicadores inflamatórios e a reatividade endotelial em pacientes idosos e obesos ou com sobrepeso. Foram selecionados 79 pacientes para receber doses diárias de óleo de linhaça, óleo de oliva e óleo de girassol por 12 semanas consecutivas. Foram realizadas medidas antropométricas, bioquímicas e de reatividade endotelial antes e após a intervenção, sem nenhuma modificação na dieta dos participantes ou em suas medicações utilizadas, não havendo mudanças antropométricas após a conclusão do estudo. Houve melhora em alguns parâmetros bioquímicos com o óleo de linhaça, que reduziu os níveis de PCRus, C3, C4 e fibrinogênio; com o óleo de girassol, que reduziu os níveis de leptina, ApoB e também a relação Apo B/ApoA1; e com o óleo de oliva que beneficiou a relação Apo B/ApoA1 e os níveis de C4. A espessura da artéria carótida também teve melhora significativa com os três óleos suplementados, mais acentuada com o óleo de linhaça e o óleo de oliva. Além disto, o óleo de girassol melhorou significativamente a distensibilidade da parede arterial e da vasodilatação fluxo-mediada (VFM) e o óleo de oliva apresentou tendência de melhora na VFM. Concluímos que a suplementação de ácidos graxos insaturados provenientes dos três óleos vegetais atenuou o quadro pró-inflamatório e pró-trombótico. Ocorreu melhora do perfil de marcadores bioquímicos e resultados significativos estatisticamente nos marcadores de reatividade endotelial como redução da espessura da íntima-média da artéria carótida, melhora da distensibilidade da parede arterial e melhora da funcionalidade medida pela VFM. Foi benéfica sua introdução à dieta, a fim de reduzir o risco cardiovascular em idosos portadores de obesidade ou sobrepeso
Obesity is a chronic disease with complications for which treatment and prevention are sought. Visceral fat is an endocrine organ of hormonal storage and a producer of inflammatory adipokines, leading to chronic inflammation in the obese person, which in turn is one of the characteristics of atherogenesis and aging. Increased levels of multifunctional cytokines, interleukin-6 and tumor necrosis factor-alfa are associated with morbidity and mortality in the elderly, and in the pathogenesis of atherosclerosis. Currently, food worldwide is characterized by increased consumption of saturated and trans fats, as well as reduced consumption of omega-3 fatty acids. Imbalance in the omega-6/omega-3 ratio provides an environment of chronic inflammation, and the initial stimulus for degenerative diseases. The substitution of saturated fats by polyunsaturated fatty acids, alfa-linolenic acid (ALA)- omega-3, and mono-unsaturated fatty acid (omega-9 fatty acids), seems to be associated with reduced risk of cardiovascular disease. Obtaining alfa-linolenic acid from vegetable sources is more financially accessible and widely available worldwide than omega-3 fatty acids from fish; both are sources of eicosapentaenoic acid and docosahexaenoic acid. This study was designed to comparatively evaluate the effect of increased ALA consumption, derived from vegetables, on inflammatory indicators and the endothelial reactivity in obese or overweight elderly patients. Seventy nine patients were selected to receive daily doses of linseed oil, olive oil and sunflower oil for 12 consecutive weeks. Anthropometric, biochemical and endothelial reactivity measurements were performed before and after the intervention, without any changes in the participants\' diet or in their medications, and no anthropometric changes were identified after the conclusion of the study. Improvement in some biochemical parameters were identified with linseed oil, which reduced the levels of C-reactive protein, C3, C4 and fibrinogen; with sunflower oil, which reduced levels of leptin, ApoB and also ApoB/ApoA1 ratio; and with the olive oil that improved the ApoB/ApoA1 ratio and the C4 levels. Carotid artery thickness also showed a significant improvement with the three supplemented oils, and was more accentuated with linseed oil and olive oil. In addition, sunflower oil significantly improved the distensibility of the arterial wall and its flow-mediated dilatation (FMD), and olive oil showed a tendency for improvement in FMD. We concluded that the supplementation of unsaturated fatty acids from the three vegetable oils attenuated the pro-inflammatory and prothrombotic conditions. An improvement in the profile of biochemical markers and statistically significant results was identified in markers of endothelial reactivity, such as reduction of carotid artery intima-media thickness, improvement of the arterial wall distensibility and the endothelial function measured by FMD. The introduction of unsaturated fatty acids in the diet was beneficial, in order to reduce cardiovascular risk in obese or overweight elderly

碩士
國立臺灣大學
醫學工程學研究所
100
Background and purpose: Patients with diabetes mellitus have the characteristics of hyperglycemia and dyslipidemia, leading to an increase in oxidative stress and a decrease in nitric oxide (NO) bioavailability. These can cause endothelial dysfunction, which is an important process in the pathogenesis of cardiovascular diseases in diabetes. Statins, inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are often utilized in the prevention of cardiovascular diseases by their efficacy at lowering lipid levels. Statins may also reduce the incidence of cardiovascular events by their non-lipid or pleiotropic effects. It has been reported that low-dose therapy by atorvastatin (Ator), one of currently available statins, did not alter the lipid profile but led to a reduction in oxidative stress. The aim of the current study was to determine whether such a low-dose Ator could produce benefits on the mechanical properties of arterial system through its decrease of oxidative stress in streptozotocin (STZ)-induced diabetic rats. Methods: Diabetes was induced in male Wistar rats at two monthes by a single tail vein injection of STZ 55 mg kg-1. After induction of hyperglycemia, the diabetic rats daily treated with Ator 10 mg kg-1 for six weeks by oral gavage were compared with the untreated age-matched diabetic controls. Pulsatile aortic pressure and flow signals were measured to describe the physical properties of the arterial system along with the pulse wave reflection phenomena. At the end of the experiment, blood and tissue samples were collected to obtain the plasma levels of free fatty acid (FFA), total cholesterol and the plasma and tissue levels of malondialdehyde/thiobarbituric acid reactive substances (MDA/TBARS). Results: In the absence of any significant changes in total cholesterol, the low dosage of Ator used in this study lowered the plasma levels of free fatty acid and the plasma and tissue levels of MDA/TBARS in diabetes. After exposure to Ator, the STZ-induced diabetic rats showed no significant changes in aortic pressure profile, basal heart rate, cardiac output and total peripheral resistance. Meanwhile, aortic characteristic impedance but not aortic compliance increased markedly in response to Ator therapy in the diabetic animals. As for wave reflection phenomena, Ator exhibited significant changes in both wave transit time by +15.4% (P<0.05) and wave reflection factor by -33.5% (P<0.001). These suggested that Ator may attenuate the diabetes-induced augmentation in systolic load imposed on the heart. The decline in systolic load by Ator treatment could be responsible for the prevention of the diabetes-related cardiac hypertrophy, as manifested by the diminished ratio of left ventricular weight to body weight. Conclusion: Our data suggest that low-lose Ator therapy may attenuate the diabetes-induced aortic stiffening and cardiac hypertrophy, possibility through its decrease of lipid oxidation-derived MDA/TBARS but not related to the total cholesterol-lowering effects of Ator in the STZ-diabetic rats.

碩士
臺灣大學
生理學研究所
98
Background: Persistent hyperglycemia, dyslipidemia and carnitine deficiency contribute to enhanced oxidative stress, which causes arterial dysfunction in diabetes mellitus. Acetyl-l-carnitine (ALC) has the best antioxidant capacity among carnitine derivates and has similar action on fatty acid metabolism. Although ALC has been proven to be beneficial for diabetic neuropathy, little attention has been given to the pulsatile hemodynamic responses to ALC in preventing diabetes-associated vascular complications. Herein, we determined the effects of ALC on physical properties of the arterial system in streptozotocin (STZ)-induced diabetes in Wistar rats, using aortic impedance analysis. In addition, the influences of ALC in diabetes-derived lipid peroxidation and abnormal lipid profiles were also measured. Materials and methods: Diabetes was induced in Wistar-Kyoto rats by a single tail vein injection with STZ (55 mg kg-1). After induction of hyperglycemia and stabilization for 2 weeks, animals were daily treated with ALC (150 mg kg-1 in drinking water) for 8 weeks and compared with the untreated aged-matched diabetic controls. Results: After exposure to ALC, the STZ-diabetic rats showed no alterations in total peripheral resistance and aortic characteristic impedance. In contrast, treatment of this experimental diabetic rats with ALC resulted in a significant rise in wave transit time, from 21.04±0.34 to 24.23±0.55 ms (P<0.001) and a fall in wave reflection factor, from 0.71±0.04 to 0.47±0.03 (P<0.001). Moreover, rising circulating NEFA and triglycerides concentration and increasing malondialdehyde (MDA) content in plasma and aortas of diabetes rats were decreased in ALC treatment group. These suggested that ALC might attenuate the diabetes-derived augmentation in systolic load of left ventricular coupled to its arterial system possibly correlating with its metabolic and antioxidant property per se. The ratio of left ventricular weight to body weight, an indicator of cardiac hypertrophy was also attenuated by the action of ALC in diabetic rats, from 2.46±0.05 to 2.01±0.04 mg g-1 (P<0.001). Conclusions: We conclude that long-term supplementation of ALC to diabetic rats imparts significant protection against the diabetes-related deterioration in ventricular loading conditions and wave reflection phenomena properly via alleviating the increasing oxidative stress in the STZ-induced rats.

Introduction: Exercise training is potentially recommended to improve heart rate variability (HRV) and arterial stiffness (AS) in coronary artery disease patients (CADp). Purposes: To analyse the acute and chronic effects of exercise stimuli (acute: A- maximal, B- bouts; chronic: C- training) on cardiac-ANS and AS in CADp. Methods: Participants: A- participants classified according to cardiorespiratory fitness: Untrained CADp as Very Poor-Fit (VPFIT-CAD; n=18); Trained CADp as Poor-Fit (PFIT-CAD; n=18); Trained healthy match individuals as Fair-Fit (FFIT-HY; n=18); B- trained CADp (CAD-t, n=18) and trained healthy individuals (HY-t, n=18); C- trained CADp divided in periodized (n=12) and non-periodized (n=12) groups. Exercise protocol: A- maximal ramp protocol; B- moderate (MOCEB) and high intensity (HICEB) combined exercise bouts; C-. periodized and non-periodized training. Results: A- CADp and healthy peers had similar HRV decrease, and AS increase during recovery. B- HICEB increased aortic- pulse wave velocity (PWV) and decrease high-frequency parameters during recovery in CAD-t; group-effect was found after HICEB on upper limb-PWV; both groups had similar responses after MOCEB on HRV and AS parameters; C- Non-periodized training was more effective to improve peripheral AS; no changes in HRV parameters in both protocols, as well as VO2peak. Conclusion: AS and HRV parameters after maximal effort is not functional level-dependent on either health status-dependent in stable patients; exercise intensity is the major factor for exercise prescription in individuals with and without CAD, determining the thin frontier between acute exercise adaptation and imbalance; non-periodized is superior to periodized training to improve peripheral AS in trained CADp.
Introdução: O treino físico é potencialmente recomendado para aprimorar a variabilidade da frequência cardíaca (VFC) e a rigidez arterial (RA) em pacientes com doença arterial coronariana (DACp). Objetivos: Analisar os efeitos agudos e crônicos dos estímulos ao exercício (agudos: A- máximo, B- sessões; C- crônico: treinamento) na VFC e RA no DACp. Métodos: Participantes: A- participantes classificados de acordo com a aptidão cardiorrespiratória: DACp não-treinados como muito baixa (MB-DAC; n=18); DACp treinados como baixa (B-DAC; n=18); Indivíduos saudáveis treinados como razoável (R-SAU; n=18); B- DACp treinados (DAC-t, n=18) e indivíduos saudáveis treinados (SAU-t, n=18); C- DACp treinados dividido em grupos periodizado (n=12) e não-periodizado (n=12). Protocolos de exercício: A- protocolo de rampa máximo; B- sessões de exercícios combinados de moderada (SECMO) e alta intensidade (SECAL); C-. treinamento periódico e não periodizado. Resultados: A- DACp e pares saudáveis apresentaram semelhante diminuição da VFC e aumento da RA durante a recuperação. B- SECAL aumentou a velocidade da onda de pulso (VOP) aórtico e diminuiu os parâmetros de alta-frequência durante a recuperação em DAC-t; o efeito do grupo foi encontrado após SECAL na VOP do membro superior; ambos os grupos tiveram respostas semelhantes após o SECMO nos parâmetros de VFC e RA; C- Treinamento não-periodizado foi mais eficaz para aprimorar a RA periférica; nenhuma alteração encontrada nos parâmetros da VFC em ambos os protocolos, bem como no VO2pico. Conclusão: Os parâmetros RA e VFC após o esforço máximo não dependem do nível funcional e do estado de saúde em pacientes estáveis; a intensidade do exercício é o principal fator para a prescrição do exercício em indivíduos com e sem DAC, o que determina a fina fronteira entre adaptação e desequilíbrio agudo ao exercício; treino não-periodizado é superior ao periodizado para aprimorar a RA periférica em DACp treinados.