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

Risk stratification guided by the index of microcirculatory resistance and left ventricular end-diastolic pressure in acute myocardial infarction

Background: The index of microcirculatory resistance (IMR) of the infarct-related artery and left ventricular end-diastolic pressure (LVEDP) are acute, prognostic biomarkers in patients undergoing primary percutaneous coronary intervention. The clinical significance of IMR and LVEDP in combination is unknown. Methods: IMR and LVEDP were prospectively measured in a prespecified substudy of the T-TIME clinical trial (Trial of Low Dose Adjunctive Alteplase During Primary PCI). IMR was measured using a pressure- and temperature-sensing guidewire following percutaneous coronary intervention. Prognostically established thresholds for IMR (>32) and LVEDP (>18 mm Hg) were predefined. Contrast-enhanced cardiovascular magnetic resonance imaging (1.5 Tesla) was acquired 2 to 7 days and 3 months postmyocardial infarction. The primary end point was major adverse cardiac events, defined as cardiac death/nonfatal myocardial infarction/heart failure hospitalization at 1 year. Results: IMR and LVEDP were both measured in 131 patients (mean age 59±10.7 years, 103 [78.6%] male, 48 [36.6%] with anterior myocardial infarction). The median IMR was 29 (interquartile range, 17–55), the median LVEDP was 17 mm Hg (interquartile range, 12–21), and the correlation between them was not statistically significant (r=0.15; P=0.087). Fifty-three patients (40%) had low IMR (≤32) and low LVEDP (≤18), 18 (14%) had low IMR and high LVEDP, 31 (24%) had high IMR and low LVEDP, while 29 (22%) had high IMR and high LVEDP. Infarct size (% LV mass), LV ejection fraction, final myocardial perfusion grade ≤1, TIMI (Thrombolysis In Myocardial Infarction) flow grade ≤2, and coronary flow reserve were associated with LVEDP/IMR group, as was hospitalization for heart failure (n=18 events; P=0.045) and major adverse cardiac events (n=21 events; P=0.051). LVEDP>18 and IMR>32 combined was associated with major adverse cardiac events, independent of age, estimated glomerular filtration rate, and infarct-related artery (odds ratio, 5.80 [95% CI, 1.60–21.22] P=0.008). The net reclassification improvement for detecting major adverse cardiac events was 50.6% (95% CI, 2.7–98.2; P=0.033) when LVEDP>18 was added to IMR>32. Conclusions: IMR and LVEDP in combination have incremental value for risk stratification following primary percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02257294

Dapagliflozin versus metolazone in heart failure resistant to loop diuretics

Background and Aims: To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide. Methods: A multi-centre, open-label, randomized, active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 hours). The primary endpoint was diuretic effect, assessed by change in weight (kg). Secondary endpoints included change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. Results: 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 hours was 976 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 hours was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; p=0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) versus 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; p=0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. Conclusion: In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. ClinicalTrials.gov Identifier: NCT04860011

Hypoxic Pulmonary Vasoconstriction in Humans:Tale or Myth

Hypoxic Pulmonary vasoconstriction (HPV) describes the physiological adaptive process of lungs to preserves systemic oxygenation. It has clinical implications in the development of pulmonary hypertension which impacts on outcomes of patients undergoing cardiothoracic surgery. This review examines both acute and chronic hypoxic vasoconstriction focusing on the distinct clinical implications and highlights the role of calcium and mitochondria in acute versus the role of reactive oxygen species and Rho GTPases in chronic HPV. Furthermore it identifies gaps of knowledge and need for further research in humans to clearly define this phenomenon and the underlying mechanism

Prognostic value of cardiac magnetic resonance parameters and biomarkers following myocardial infarction; 10 year follow‐up of the Eplerenone Remodeling in Myocardial Infarction without Heart Failure trial

No abstract available

Ionenstrahlmischen: Grundlegende Abstimmung von PVD-Verfahren auf das Ionenstrahlmischen Entwicklung von standardisierten Tests. Schlussbericht

With 7 figs.Available from TIB Hannover: D.Dt.F. AC1000(43,40) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

The emerging potential of the apelin-APJ system in heart failure

The apelin-APJ system is a novel neurohormonal pathway, with studies to date suggesting that it may be of pathophysiologic relevance in heart failure and may indeed be a viable therapeutic target in this syndrome. This interest is driven primarily by the demonstration of its vasodilator, inotropic, and aquaretic actions as well as its apparent antagonistic relationship with the renin-angiotensin system. However, its promise is heightened further by the observation that, unlike other and more established cardioprotective pathways, it appears to be down-regulated in heart failure, suggesting that augmentation of this axis may have a powerful effect on the heart failure syndrome. We review the literature regarding the apelin-APJ system in heart failure and suggest areas requiring further research

Interleukin-21 – a biomarker of importance in predicting myocardial function following acute infarction?

Introduction Following acute myocardial infarction (AMI), the acute inflammatory response contributes to wound healing but also to progressive myocardial injury. Interleukin-21 (IL-21) plays a key role in immunoregulation; whether IL-21 is associated with left ventricular (LV) remodelling after AMI is unknown. Methods Plasma IL-21 concentrations were measured in 100 patients (age 58.9 ± 12.0 years, 77% male) admitted with AMI and LV dysfunction, at baseline (mean 46 h) and again at 24 weeks; cardiac magnetic resonance and measurement of B-type natriuretic peptide, monocyte chemoattractant protein-1, matrix metalloproteinase (MMP)-2, -3, -9, and tissue inhibitor of metalloproteinase (TIMP)-1, -2, -4 occurred at both time-points. Remodelling was defined as change in LV end-systolic volume index (ΔLVESVI). Results Plasma IL-21 concentration was unchanged over time (48.1 [SD 35.4] pg/mL at baseline vs. 48.8 [61.3] pg/mL at 24 weeks, p = 0.92). Baseline IL-21 correlated significantly with ΔLVESVI (r = 0.30, p = 0.005) and change in LV end-diastolic volume index (r = 0.33, p = 0.003). On multivariate analysis, plasma IL-21 was an independent predictor of remodelling. IL-21 was also significantly associated with higher TIMP-4 concentrations and lower MMP-9 concentrations at baseline. Conclusions IL-21 predicts adverse remodelling following AMI in patients with LV dysfunction. Whether it plays a direct pathophysiological role in remodelling merits further study. </p