Mineralocorticoid Receptor Blockade Attenuates Chronic Overexpression of the Renin-Angiotensin- Aldosterone System Stimulation of Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Cardiac Remodeling

doi: 10.1210/en.2006-1691The renin-angiotensin-aldosterone system contributes to cardiac remodeling, hypertrophy, and left ventricular dysfunction. Angiotensin II and aldosterone (corticosterone in rodents) together generate reactive oxygen species (ROS) via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which likely facilitate this hypertrophy and remodeling. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo mineralocorticoid receptor (MR) blockade in a rodent model of the chronically elevated tissue renin-angiotensin-aldosterone system, the transgenic TG (mRen2) 27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, proteinuria, and cardiovascular damage. Young (6- to 7-wk-old) male Ren2 and age-matched Sprague-Dawley rats were treated with spironolactone or placebo for 3 wk. Heart tissue ROS, immunohistochemical analysis of 3-nitrotyrosine,and NADPH oxidase (NOX) subunits (gp91phox recently renamed NOX2, p22phox, Rac1, NOX1, and NOX4) were measured. Structural changes were assessed with cine-magnetic resonance imaging, transmission electron microscopy, and light microscopy. Significant increases in Ren2 septal wall thickness (cine-magnetic resonance imaging) were accompanied by perivascular fibrosis, increased mitochondria, and other ultrastructural changes visible by light microscopy and transmission electron microscopy. Although there was no significant reduction in systolic blood pressure, significant improvements were seen with MR blockade on ROS formation and NOX subunits (each P < 0.05). Collectively, these data suggest that MR blockade, independent of systolic blood pressure reduction, improves cardiac oxidative stress-induced structural and functional changes, which are driven, in part, by angiotensin type 1 receptor-mediated increases in NOX.This research was supported by National Institutes of Health (NIH) Grants R01 HL73101-01A1 (to J.R.S.) and P01 HL-51952 (to C.F.), the Veterans Affairs Merit System (0018) (to J.R.S.), and Advanced Research Career Development (to C.S.). Male transgenic Ren2 rats and male Sprague-Dawley controls were kindly provided by C.F. through the Transgenic Core Facility supported in part by NIH Grant HL-51952

Aldosterone Modulates Cell Proliferation and Apoptosis in the Neonatal Rat Heart

In the present study, we investigated whether and how the mineralocorticoid receptor antagonist spironolactone affects cardiac growth and development through apoptosis and cell proliferation in the neonatal rat heart. Newborn rat pups were treated with spironolactone (200 mg/kg/d) for 7 days. The cell proliferation was studied by PCNA immunostaining. The treatment with spironolactone decreased proliferating myocytes by 32% (P<0.05), and reduced myocytes apoptosis by 29% (P<0.05). Immunoblot and immunohistochemistry for the expression of p38, p53, clusterin, TGF-β2, and extracellular signal-regulated kinase were performed. In the spironolactone group, p38, p53, clusterin, and TGF-β2 protein expression was significantly decreased (P<0.05). These results indicate that aldosterone inhibition in the developing rat heart induces cardiac growth impairment by decreasing proliferation and apoptosis of myocytes

The role of cardiac myocyte dimensions in the transition from hypertensive hypertrophy to cardiac dilatation

The progression from compensated cardiac hypertrophy to decompensation and cardiac failure is accompanied by cardiac dilatation. As cardiac failure has a poor prognosis, it is imperative to prevent the progression to cardiac dilatation and heart failure. In this regard, an understanding of the mechanisms of cardiac dilatation is vital to guide optimal therapy to prevent heart failure. Although a number of factors have been shown to contribute to the development of cardiac dilatation, to date the role of alterations in cardiac myocyte dimensions remains unclear. Hence, the aim of the current study was to determine whether changes in cardiac myocyte dimensions contribute to the process of cardiac dilatation. Methods: Two models of cardiac dilatation in pressure-overload induced cardiac hypertrophy were assessed. One model was a natural progression model, in which 18 spontaneously hypertensive rats (SHR), were assessed at 23 months of age (an age when left ventricular hypertrophy is noted to have progressed to left ventricular decompensation, dilatation and heart failure in approximately 50% of rats). The second model, a pharmacological model, was induced in 14 month old SHR (n=9) by chronic beta-adrenoreceptor activation [0.02mg/kg isoproterenol (ISO) twice daily for 4.5 months]. Chronic beta-adrenoreceptor activation in SHR, enhances the progression from compensated left ventricular hypertrophy to left ventricular dilatation. Nine normotensive Wistar Kyoto (WKY) rats were the controls for both models. Left ventricular dilatation was defined as an increase in left ventricular radius determined at controlled filling pressures using piezo-electric transducers. The classification of rats as being in heart failure was based upon the presence of pleuropericardial effusions and / or atrial thrombi. Cardiac myocytes were isolated and dimensions determined using both light microscopy and flow cytometry. Results: Left ventricular radius was increased in SHR-Failure compared to SHR-Non-Failure (p<0.01), and in SHR-ISO compared to SHR-Control (saline administration) (p<0.01), hence confirming the presence of cardiac dilatation in both models. Although, cardiac myocyte length was increased in all SHR groups compared to WKY (p<0.001), no differences were observed between SHR-Failure and SHR-Non-Failure, or between SHR-ISO and SHR-Control. No differences in cell length:width ratios or in cell widths were evident between the groups. The flow cytometry data confirmed the results obtained for cardiac myocyte lengths using microscopy. Moreover, a linear correlation (r=0.46, p=0.002) between flow cytometry and microscopy cardiac myocyte lengths was observed. Importantly, no relationships were evident between left ventricular radius and cardiac myocyte length (r=0.12, p=0.42 and r=0.14, p=0.35 for microscopic and flow cytometry lengths respectively). Conclusion: The results from the present study show that although pressure-overload hypertrophy is associated with lengthening of cardiac myocytes, no further changes occur with cardiac dilatation. Hence, alterations in cardiac myocyte dimensions do not contribute to the development of cardiac dilatation in pressure-overload models

Reverse remodelling in a rat model of ardrenergic-induced cardiac dilatation and pump dysfunction

M.Sc. (Med.)--Faculty of Health Sciences, University of the Witwatersrand, 2011In-part through a decrease in cardiac cavity dimensions (reverse remodelling), β-adrenergic receptor blockers have been demonstrated to produce marked benefits to morbidity and mortality in patients with chronic heart failure. However, maximum doses of these agents are often difficult to achieve in patients with chronic heart failure because of the negative inotropic, hypotensive and other side effects. Whether blockade of the excessive adrenergic effects achieves complete reverse remodelling in progressive heart failure is nevertheless uncertain. To test this hypothesis I simulated the adverse effects of chronic adrenergic stimulation on the heart by administering daily doses of the β-adrenergic receptor agonist, isoproterenol (ISO) (2.42 X 10-8 mmol.kg-1) to rats for 6 months and compared left ventricular (LV) dimensions and systolic function to Saline-vehicle treated rats. To imitate the effects of complete adrenergic receptor blockade following the development of adrenergic-induced adverse cardiac changes, I similarly administered ISO for 6 months and then subsequently withdrew the daily ISO administration for a further 4 months (ISO+Recovery) before comparing left ventricular dimensions and function to Saline+Recovery treated rats. In comparison to a Saline vehicle-treated group, after 6 months of ISO administration, LV end diastolic and systolic diameters, and the volume intercept of the left ventricular diastolic pressure-volume relationship (LV V0), were markedly increased and LV endocardial fractional shortening (FSend), LV end systolic chamber (slope of the systolic pressure-volume relationship-Ees) and myocardial (slope of the systolic stress-strain relationship-En) contractility were substantially decreased. The extent of the adverse remodelling produced by chronic ISO administration was exemplified by the 2.5 times increase in LV V0 (ISO=0.40±0.04 vs Saline=0.16±0.01, p<0.001), a change proportionate to that noted in humans with chronic heart failure. iii The proportion of ISO-treated rats with LV chamber diameters, and LV V0 values above the 95% confidence interval for Saline-treated rats was markedly greater than the proportion of Saline-treated rats above their own 95% confidence intervals. Moreover, the proportion of ISO-treated rats with FSend, LV Ees and LV En values below the 95% confidence interval for Saline-treated rats was markedly greater than the proportion of Saline-treated rats below their own 95% confidence intervals. Following a 6 month period of ISO administration and a subsequent period of withdrawal of ISO administration for a further 4 months, LV chamber diameters, LV V0, FSend, LV Ees and LV En were all noted to be similar to age-matched Saline+Recovery control rats. Indeed, the increases in LV V0 observed after 6 months of ISO administration were completely reversed (ISO+Recovery=0.21±0.02 vs Saline=0.23±0.02, p<0.001). The proportion of ISO+Recovery rats with LV chamber diameters, and LV V0 values above the 95% confidence interval for the Saline+Recovery rats was similar to the proportion of Saline+Recovery rats above their own 95% confidence intervals. Moreover, the proportion of ISO+Recovery rats with FSend, LV Ees and LV En values below the 95% confidence interval for Saline+Recovery rats was similar to the proportion of Saline+Recovery rats below their own 95% confidence intervals. Chronic ISO administration and the withdrawal of ISO administration was not associated with changes in myocardial necrosis (pathological score and myocardial collagen concentrations). In conclusion, marked cardiac dilatation and pump dysfunction produced by chronic β-adrenergic receptor activation can be completely reversed by withdrawal of the excessive adrenergic stimulus. These data highlight the importance in chronic heart failure of achieving complete blockade of the pathways activated by excessive β-adrenergic receptor stimulation even in individuals with advanced cardiac dilatation

Regulated necrosis in the adrenal glands and the kidney

Regulated cell death (RCD) is indispensable for homeostasis and plays a crucial role in the pathophysiology of numerous diseases. Adrenocortical carcinomas (ACCs) represent a rare and highly malignant type of cancer. Currently, the most common therapeutic options include the complete surgical removal of the adrenal gland and/or the administration of mitotane, a derivative of the pesticide DDT. Yet patient survival remains poor and the mechanism of action of mitotane remains elusive. In this thesis it is demonstrated that the human ACC cell line NCI-H295R is sensitive to mitotane-induced cell death. In the first part, the involvement of three different RCD pathways, namely apoptosis, necroptosis and ferroptosis, in mitotane induced necrosis was investigated. To this end, different inhibitors were used, which were not able to block mitotane-induced cell death. When the medium was supplemented with insulin, transferrin, sodium selenite and linoleic acid (ITS+1) no cell death of the ACC cells was observed. This phenomenon was attributed to the presence of linoleic acid, since ITS supplementation lacking this component was not able to reverse mitotane-induced necrosis. Identification of new drug targets for alternative options of ACC treatment led to the investigation of key molecules involved in the pathways of necroptosis and ferroptosis. The receptor-interacting protein kinase 1 and 3 (RIPK1 and 3) and the mixed lineage kinase domain-like protein (MLKL) were considered as interesting targets given their crucial role in the execution of necroptosis. A western blot analysis of those molecules revealed the presence only of RIPK1, suggesting that the necroptosis machinery is not present in the NCI-H295R cells. Of interest, evaluation of the expression levels of glutathione peroxidase four (GPX4), one of the main inhibitory molecules of ferroptosis, showed a much higher expression in the ACC cells compared to the standard cell line used for studying ferroptosis, the human fibrosarcoma HT1080 cells. A hypothesis that the NCI-H295R cells are susceptible to ferroptosis induction was formed based on this finding. Compounds representative of all the four classes of ferroptosis inducers (FINs) were tested. Direct inhibition of GPX4 using the small compound RSL3, a type II FIN, led to high necrotic populations. Co-treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) completely reversed RSL3-induced ferroptosis. Type IV FIN FINO2, that causes indirect loss of the enzymatic activity of GPX4, lead also to high necrotic populations, while Fer-1 prevented FINO2-induced ferroptosis. Data from public databases concerning gene methylation or mutation status of ACC tissues and normal human adrenal tissues was used to investigate potential key players of ferroptosis that might be either mutated or silenced in ACCs. Of note, glutathione peroxidases 3 and 5 (GPX3 and 5) were highly methylated, while the enzyme cystathionine gamma-lyase (CSE) involved in the transsulfuration pathway via the break down of cystathionine into cysteine and α-ketobutyrate and ammonia was found to be highly mutated. Collectively, these data point towards a high sensitivity of ACCs to ferroptosis induction. This could provide a new chapter for the therapeutic approaches of ACCs. Additionally, these findings provide a better understanding of the biology of this type of cancer that highly mutates or silences ferroptosis-related genes. The second part of this thesis focuses on the involvement of RCD in spontaneous cell death in isolated murine tubules. Existing literature points towards an involvement of necroptosis and ferroptosis pathways in the kidney in models of acute kidney injury (AKI). Acute tubular necrosis (ATN) represents a hallmark of AKI. While the work in the Linkermann lab has shown that isolated tubules perfused with type I FIN erastin undergo cell death in a “wave-of-death” manner, no deeper insights into the propagation of tubular necrotic injury exist. A protocol for isolation of murine kidney tubules was established, providing an ex-vivo model for investigation of tubular death. The absence of potentially confounding blood cells as well as immune cells was ensured by extensive washing steps as well as the use of collagenase. Visual observation and staining of isolated tubules with the nucleic acid stain SYTOX green revealed a spontaneous cell death in a “wave-of-death” manner. This wave was running in parallel with a calcium concentration change, indicating its involvement in the spontaneous necrosis. To investigate the potential involvement of mitochondria in this process, electron microscopy images were obtained from parts of the tubules with different levels of damage which revealed highly damaged and ballooned mitochondria. These data provided with a phenotypic characterisation of the spontaneous tubular necrosis. Aiming to approach this type of death genetically, necroptosis and pyroptosis deficient mice (MLKL/GSDMDDKO) were used. Comparison of the LDH release, used as a measure of necrosis, from isolated kidney tubules of the MLKL/GSDMDDKO mice and wild type (WT) mice showed no difference. This indicated that neither necroptosis nor pyroptosis are involved in the tubular necrosis. Therefore, the next step was to investigate the effects of Fer-1 at the levels of LDH of isolated tubules from WT mice. A significantly lower LDH release was observed in tubules treated with Fer-1 compared to the ones treated with vehicle. However, this reduction in the LDH release was not complete, suggesting that ferroptosis is only partially responsible for the spontaneous death of isolated tubules. The difference of male and female mice towards AKI sensitivity has been noted in the literature in that female mice are less susceptible compared to the male mice. Therefore, the next step was to investigate whether this protection of females can be observed at the level of isolated tubules. Indeed, the LDH release from tubules isolated from female mice was significantly less compared to the LDH release of tubules isolated from male mice. Based on the data obtained from isolated tubules from WT male mice treated with Fer-1, a similar experiment was performed with tubules isolated from WT female mice. No difference in the LDH release was observed between the Fer-1-treated tubules and the vehicle-treated ones, indicating that another cell death pathway might be involved. The most obvious difference between male and female organisms is the sex hormones. Whether testosterone or β-estradiol are responsible for the higher susceptibility or protection against cell death has been a debate over the last years. To test this hypothesis, three different cell lines were utilised. A pre-treatment of 16 h with either testosterone or β-estradiol was performed. Treatment with either type I FIN erastin or type II FIN RSL3 followed, and cells were analysed via flow cytometry. Data revealed protective effects of β-estradiol against ferroptosis induction. Next, the effects of β-estradiol in a simultaneous treatment with RSL3 were investigated. Interestingly the protective effects of the hormone were still observed. Among the metabolites of β-estradiol, 2-hydroxyestradiol (2-OHE2) has been reported to exert antioxidant effects. Therefore, 2-OHE2 was used in a simultaneous treatment with RSL3, and the obtained data showed that it was a much more potent inhibitor of necrotic cell death than β-estradiol even at lower concentrations. Collectively these data indicate that the lower susceptibility of female organisms towards cell death might be explained by the presence of β-estradiol and its more potent antioxidant metabolites. Such findings could change the way the two sexes are approached scientifically, while providing new insights on different therapeutic strategies between male and female organisms

Impact of excess adiposity on blood pressure and cardiovascular target organ damage

Ph.D., Faculty of Health Sciences, University of the Witwatersrand, 2009Epidemiological trends suggest that obesity is becoming a major public health problem. Although obesity contributes toward cardiovascular risk by promoting the development of hypertension, dyslipidaemia and diabetes mellitus (conventional risk factors), there is increasing evidence to suggest that excess adiposity may increase risk through effects on cardiovascular target organs that are independent of conventional risk factors. These obesity-induced effects may be produced by mediating damage and dysfunction of large vessels and the heart, and by promoting the development of cardiac hypertrophy. However, the independent effect of excess adiposity on large vessels has not been confirmed in all studies. Moreover, whether the impact of excess adiposity on cardiac hypertrophy or cardiac damage and dysfunction is dependent on an interaction with blood pressure (BP) is uncertain. In the present thesis I addressed these questions. Before evaluating these questions I first identified the preferred clinical index of adiposity when predicting BP. In this regard, some, but not all studies support the notion that indexes of central adiposity (waist circumference or waist-to-hip ratio) are the preferred predictors of conventional BP over indexes of general (body mass index) or subcutaneous (skin-fold thickness) adiposity. Moreover, to my knowledge no study has been conducted in a large study sample to evaluate whether indexes of central adiposity are the preferred predictors of ambulatory BP, a measure of BP that is more closely associated with cardiovascular events than conventional BP. In the first study conducted in a relatively large, randomly selected population sample (n=300) with a high prevalence of excess adiposity (65%), I demonstrated that waist circumference is the only clinical index of adiposity that is associated with an increased conventional and ambulatory systolic and diastolic BP, independent of other indexes of adiposity. With regards to the effects of excess adiposity on large arteries, there is inconsistency in the reports demonstrating relations between indexes of adiposity and large artery dysfunction (arterial stiffness) independent of factors such as BP, heart rate and diabetes mellitus. As convincing independent relations between clinical indexes of adiposity and arterial stiffness have been noted in older, but not in younger populations, I hypothesized that age may determine whether excess adiposity promotes increases in arterial stiffness independent of confounders. Indeed, in 508 randomly selected persons from a population sample with a high prevalence of excess adiposity (~63% overweight or obese), I was able to show that age markedly influenced the independent relationship between indexes of central adiposity and an index of large artery stiffness in women but not in men after adjusting for confounders. The adjusted effect of indexes of central obesity on arterial stiffness was ~5-fold higher in older than in younger women. With respect to the impact of excess adiposity on cardiac growth, although severe obesity is associated with an enhanced impact of BP on left ventricular mass (LVM), there is uncertainty as to whether the same effects occur in milder forms of excess adiposity, data confounded by the high prevalence of participants receiving antihypertensive therapy in previous studies. In the present thesis I demonstrated in a randomly recruited population sample of 398 participants with a high prevalence of mild-to-moderate obesity and hypertension (~41%), but in whom antihypertensive use was limited (~17%), that adiposity is indeed associated with an enhanced impact of conventional and ambulatory BP or arterial stiffness on LVM index and wall thickness independent of additional conventional risk factors. With regards to the impact of obesity on cardiac function, although obesity is a risk factor for heart failure independent of other conventional cardiovascular risk factors, whether this effect occurs through changes in cardiac systolic chamber function is uncertain. In the present thesis I provide the first evidence to show in an animal model of genetic iv hypertension and dietary-induced obesity, that dietary-induced obesity promotes the progression from compensated cardiac hypertrophy to cardiac pump dysfunction without promoting hyperglycaemia. This effect was attributed to alterations in both intrinsic myocardial systolic dysfunction and cardiac dilatation, effects that were associated with excessive cardiomyocyte apoptosis and activation of enzymes that promote myocardial collagen degradation. Therefore in the present thesis I provide evidence to support the notion that waist circumference should hypertension and dietary-induced obesity, that dietary-induced obesity promotes the progression from compensated cardiac hypertrophy to cardiac pump dysfunction without promoting hyperglycaemia. This effect was attributed to alterations in both intrinsic myocardial systolic dysfunction and cardiac dilatation, effects that were associated with excessive cardiomyocyte apoptosis and activation of enzymes that promote myocardial collagen degradation. Therefore in the present thesis I provide evidence to support the notion that waist circumference should be measured when predicting BP changes, that excess adiposity does indeed decrease large vessel function independent of conventional risk factors, but that this effect is age-dependent, and that the deleterious effects of excess adiposity on cardiac hypertrophy and cardiac pump function are indeed dependent on an interaction with BP, but not other confounders

Pathophysiological role of aldosterone in cardiac remodelling after myocardial infarction

Acute myocardial infarction (AMI) remains a common and serious manifestation of coronary artery disease. The development of heart failure (HF) and/or evidence of left ventricular systolic dysfunction (LVSD) following AMI increases both in-hospital and longer-term mortality. A series of structural and functional changes occur within the heart in general and within the left ventricle (LV) in particular following AMI, initially providing a stabilising mechanism to maintain the cardiac output but over time becoming maladaptive and leading to progressive ventricular dilatation, dysfunction, HF and premature death. This process is termed remodelling. It is now understood that a complex series of mechanical, genetic and neurohormonal factors, including the mineralocorticoid hormone aldosterone, are implicated in its pathogenesis. Aldosterone antagonism reduces cardiovascular morbidity and mortality in patients with advanced chronic HF and survivors of large AMI who develop HF and/or are diabetic. These benefits could, at least in part, be due to an anti-remodelling action, although this was uncertain at the time I began my research project. The work contained in this thesis examines cardiac remodelling, and the effects of the mineralocorticoid receptor antagonist eplerenone, in a cohort of 100 patients admitted with AMI, with depressed LV ejection fraction (LVEF) but without HF or diabetes mellitus, using a gold standard modality for LV functional assessment and infarct imaging: late gadolinium-enhanced cardiac magnetic resonance (LGE-CMR). Patients were treated with (double-blinded) eplerenone or placebo for 24 weeks, and underwent serial LGE-CMR scanning and measurement of haematological, urinary and genetic markers thought to be of pathophysiological importance in post-infarction remodelling. There was, by chance, a significant imbalance in LV function at baseline between the randomised groups. After pre-specified covariate-adjustment, however, I found a significant effect of eplerenone on LV remodelling. Moreover I found that the use of eplerenone in addition to an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was well-tolerated. I also found an effect of eplerenone on two matrix metalloproteinases (MMPs) considered key enzymes in extracellular matrix turnover. Specifically, eplerenone decreased MMP-2 and attenuated the drop in MMP-9 seen in the placebo group, changes that are protective against remodelling. These findings suggest a potential anti-remodelling effect of eplerenone in ‘asymptomatic’ LVSD after AMI, i.e. patients in whom eplerenone is not currently indicated. Patients with limited functional recovery early after AMI resulting in a persistently reduced LVEF require stringent monitoring and may qualify for an implantable cardioverter defibrillator. The use of predictive biomarkers to identify such patients is gaining popularity. I found that two biomarkers, tissue plasminogen activator (tPA) antigen and tissue inhibitor of metalloproteinase-4 (TIMP-4), measured in a blood sample taken a mean of 3 days after AMI, were independent predictors of adverse remodelling. These findings are novel, provide further pathophysiological insights into the inter-related biological systems that underlie remodelling, and may inform future trials aimed at modulating these pathways in order to attenuate remodelling. LGE-CMR affords detailed characterisation of myocardium. In keeping with previous studies, infarct volume, endocardial extent and transmurality predicted LV remodelling. In addition I also found that the presence of microcirculatory dysfunction, defined as persistent microvascular obstruction (MVO) within the infarcted region on baseline LGE-CMR, divided my study population into two distinct groups with opposite remodelling outcomes. Patients with late MVO progressively remodelled, while those without reverse remodelled over 24 weeks. From these results, I propose that late MVO be used as an indicator of adverse ventricular remodelling. This may enhance the risk-stratification of survivors of AMI. Aldosterone has a number of detrimental effects on the cardiovascular system and is strongly implicated in the pathogenesis of remodelling. I observed direct correlations between aldosterone sampled at baseline and CMR parameters of remodelling. Analysis by treatment group revealed an association between change in aldosterone over time and parameters of remodelling in placebo- but not eplerenone-treated patients, despite higher circulating aldosterone concentrations in the latter group. We propose that the cardiac effects of aldosterone display a temporal variation after AMI, specifically that circulating aldosterone in the first few days after infarction is key in selecting a remodelling pathway but that over the following weeks and months circulating aldosterone is less influential in potentiating the remodelling process. I also found a novel relationship between aldosterone and infarct volume, which merits further investigation as the role of aldosterone in the pathophysiology of remodelling is further described. My trial design afforded the opportunity to examine the relationships of certain novel biomarkers with LV function and other established biomarkers after AMI. I demonstrated that circulating concentrations of the peptide apelin were reduced over 24 weeks after AMI compared to healthy controls but bore no relationship to LV function. Separately, I showed that concentrations of the soluble interleukin-1 receptor family member ST2 fell significantly over time after AMI and correlated with early and medium-term LV function and infarct volume. I detected a novel relationship between ST2 and aldosterone, which may suggest a pathophysiological role for ST2 in post-infarction remodelling and merits further investigation. These studies provide further insights into the roles of aldosterone and of selective mineralocorticoid receptor antagonism in cardiac remodelling in a relatively under-studied population: survivors of AMI with ‘asymptomatic’ LVSD. The primary results may inform clinical trials powered to detect a mortality benefit in this patient group. The data provided on the use of established and recently-discovered biomarkers in the prediction of medium-term LV function after AMI represents a highly topical area for further studies. Finally, pre-discharge CMR was safe in AMI patients, and facilitated the detection of additional findings that positively influenced the management of almost one-quarter of the trial cohort. These findings may lead to greater uptake of this increasingly-available modality, to enhance the early management and risk stratification of survivors of large AMI

Contrôle pharmacologique de l'apoptose cardiovasculaire dans l'hypertension : implication de la voie de l'angiotensine et de la correction de la dysfonction endothéliale

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