Monocyte subpopulations in patients following ST-elevation myocardial infarction:implications for post-infarction left ventricular remodelling and clinical outcomes

Despite improvements in interventional and pharmacological therapy of atherosclerotic disease,it is still the leading cause of death in the developed world. Hence there is a need for further development of effective therapeutic approaches. This requires better understanding of the molecular mechanisms and pathophysiology of the disease. Atherosclerosis has long been identified as having an inflammatory component contributing to its pathogenesis, whilst the available therapy primarily targets hyperlipidaemia and prevention of thrombosis. Acknowledging a pleotropic anti-inflammatory effect to some therapies, such as acetyl salicylic acid and the statins, none of the currently approved medicines for management of either stable or complicated atherosclerosis has inflammation as a primary target. Monocytes, as representatives of the innate immune system, play a major role in the initiation, propagation and progression of atherosclerosis from a stable to an unstable state. Animal study data support a role of monocytes in acute coronary syndromes and in outcome post infarction; however, limited research has been done in humans.  In this thesis I describe for the first time in a large cohort of ST elevation myocardial infarction(STEMI) patients followed up for three years that total monocyte count, monocyte subset 1(Mon 1), and monocyte subset 2 (Mon 2) are predictive of major adverse cardiac events (MACE)post STEMI (including death, new diagnosis of heart failure, recurrent acute coronary syndrome). Both the inflammatory function of monocyte subsets (via assessment and quantification of IKK as a surrogate for the NFB inflammatory pathway activation) as well as the phagocytic activity of monocytes were studied in order to describe the mechanism through which monocytes affect their action. There was no significant difference in the NFB pathway activity between those patients who developed an adverse event and those who did not. Also NFB activity was not predictive of MACE. However the phagocytic activity of Mon 1 and Mon 2 were predictive of MACE suggesting that phagocytic activity of monocytes is the mechanism through which monocytes implement their action. Also this supports that the newly described monocytes subset 2 (Mon 2) is predominantly an inflammatory monocyte subset, not reparative as Mon 3.  Major adverse cardiac events were driven mainly by heart failure diagnosis and echocardiographic findings. Hence the association between ventricular remodelling and phenotypic and functional characterisation of monocytes subsets was studied in this thesis. Total monocyte count, Mon 1 and Mon 2 were again predictive of negative ventricular remodelling with increase in end systolic indexed volume of >15% at 6 months follow up echocardiogram post infarction. Subclinical parameters of systolic dysfunction, namely global longitudinal strain and global circumferential strain were also significantly correlated with total monocyte count as well as Mon 1 levels.  Given the above, I studied the effect of incorporating total monocyte count in Thrombolysis in Myocardial Infarction (TIMI) STEMI score to predict patient outcome at 30 days post infraction.C- statistics indicated improved prognostication of the TIMI STEMI model after incorporation of the total monocyte count into the model with improved area under the curve from 0.67 (for TIMI STEMI score), to area under the curve of 0.77 (TIMIMon score). This allows individual tailoring of secondary preventative therapy in order to improve patient outcome post infarction.Having described a potential mechanism through which the innate immune system affects outcome in STEMI patients, namely Mon1 and Mon2 through their phagocytic activity, the results from this thesis could be a stepping stone into targeted anti-inflammatory therapy in management of myocardial infarction

Rationale and design of the effect of mineralocorticoid receptor antagonist therapy in patients with acute myocardial infarction or injury and non-obstructive coronary arteries: A registry-based, stratified-medicine, randomised, controlled trial

Background Myocardial infarction and non-obstructive coronary arteries (MINOCA) affects 1 in 9 patients with acute coronary syndrome. Vascular pathophysiology includes atherothrombosis and coronary vasomotion disorders. MINOCA has an unmet therapeutic need. Objectives To implement stratified medicine in patients with MINOCA by undertaking a prospective, registry-based, randomised, blinded end-point trial. Rationale There are no evidence-based, disease-modifying therapies for patients with MINOCA. Preventive therapy with antiplatelet drugs and statins is empirical. Coronary microvascular dysfunction, including increased microvascular resistance, impaired vasodilator reserve and vasospasm, is implicated in the pathogenesis of MINOCA. Targeted therapy may reduce myocardial injury, improve myocardial recovery and health status prospectively. The rationale is for a stratified medicine approach targeting microvascular dysfunction with eplerenone, a vasculoprotective mineralocorticoid receptor antagonist, in MINOCA patients with coronary microvascular dysfunction. Design Following informed consent, 350 patients with MINOCA will be prospectively enrolled (NCT05198791) into a registry. Coronary microvascular function will be measured during invasive angiography. Eligible patients with one or more cardiovascular risk factors and elevated index of microvascular resistance (IMR ≥25) will be randomised to receive eplerenone or standard care (n = 150) in a prospective randomised open blinded end-point design. All patients will undergo the same assessments including cardiovascular magnetic resonance imaging (MRI) within two weeks of enrolment to establish a final diagnosis. Trial patients will also be invited to undergo repeat MRI with adenosine stress perfusion at six months. Primary outcome: Registry: the proportion of patients with MINOCA and IMR ≥25; Trial: Within-subject change in NT-proBNP at pre-defined measurement time-points: baseline, 1 and 6 months. Secondary outcomes Global hyperaemic myocardial blood flow (ml/min/g tissue); patient reported outcome measures and quality of life questionnaires; health-economics questionnaires, within-subject change in markers of collagen degradation as a marker of myocardial fibrosis vascular adhesion molecules as markers of vascular inflammation. Intravascular imaging with optical coherence tomography (OCT) will be undertaken in a sub-study (n=30). Participants will be invited to take part in a vascular sub-study, undergoing gluteal subcutaneous fat biopsy to isolate and characterise small resistance artery biology. Value Novel data on stratified medicine for MINOCA and eplerenone as potential disease-modifying therapy for this condition

Outcomes in Valve-in-Valve Transcatheter Aortic Valve Implantation

: The use of valve-in-valve transcatheter aortic valve implantation (ViV-TAVI) is increasing, but studies evaluating clinical outcomes in these patients are scarce. Also, there are limited data to guide the choice of valve type in ViV-TAVI. Therefore, this CENTER-study evaluated clinical outcomes in patients with ViV-TAVI compared to patients with native valve TAVI (NV-TAVI). In addition, we compared outcomes in patients with ViV-TAVI treated with self-expandable versus balloon-expandable valves. A total of 256 patients with ViV-TAVI and 11333 patients with NV-TAVI were matched 1:2 using propensity score matching, resulting in 256 patients with ViV-TAVI and 512 patients with NV-TAVI. Mean age was 81±7 years, 58% were female, and the Society of Thoracic Surgeons Predicted Risk of Mortality was 6.3% (4.0% to 12.8%). Mortality rates were comparable between ViV-TAVI and NV-TAVI patients at 30 days (4.1% vs 5.9%, p = 0.30) and 1 year (14.2% vs 17.3%, p = 0.34). Stroke rates were also similar at 30 days (2.8% vs 1.8%, p = 0.38) and 1 year (4.9% vs 4.3%, p = 0.74). Permanent pacemakers were less frequently implanted in patients with ViV-TAVI (8.8% vs 15.0%, relative risk 0.59, 95% confidence interval [CI] 0.37 to 0.92, p = 0.02). Patients with ViV-TAVI were treated with self-expandable valves (n = 162) and balloon-expandable valves (n = 94). Thirty-day major bleeding was less frequent in patients with self-expandable valves (3% vs 13%, odds ratio 5.12, 95% CI 1.42 to 18.52, p = 0.01). Thirty-day mortality was numerically lower in patients with self-expandable valves (3% vs 7%, odds ratio 3.35, 95% CI 0.77 to 14.51, p = 0.11). In conclusion, ViV-TAVI seems a safe and effective treatment for failing bioprosthetic valves with low mortality and stroke rates comparable to NV-TAVI for both valve types

Diabetes mellitus in transfemoral transcatheter aortic valve implantation: a propensity matched analysis

Background: Diabetes Mellitus (DM) affects a third of patients with symptomatic severe aortic valve stenosis undergoing transcatheter aortic valve implantation (TAVI). DM is a well-known risk factor for cardiac surgery, but its prognostic impact in TAVI patients remains controversial. This study aimed to evaluate outcomes in diabetic patients undergoing TAVI. Methods: This multicentre registry includes data of > 12,000 patients undergoing transfemoral TAVI. We assessed baseline patient characteristics and clinical outcomes in patients with DM and without DM. Clinical outcomes were defined by the second valve academic research consortium. Propensity score matching was applied to minimize potential confounding. Results: Of the 11,440 patients included, 31% (n = 3550) had DM and 69% (n = 7890) did not have DM. Diabetic patients were younger but had an overall worse cardiovascular risk profile than non-diabetic patients. All-cause mortality rates were comparable at 30 days (4.5% vs. 4.9%, RR 0.9, 95%CI 0.8–1.1, p = 0.43) and at one year (17.5% vs. 17.4%, RR 1.0, 95%CI 0.9–1.1, p = 0.86) in the unmatched population. Propensity score matching obtained 3281 patient-pairs. Also in the matched population, mortality rates were comparable at 30 days (4.7% vs. 4.3%, RR 1.1, 95%CI 0.9–1.4, p = 0.38) and one year (17.3% vs. 16.2%, RR 1.1, 95%CI 0.9–1.2, p = 0.37). Other clinical outcomes including stroke, major bleeding, myocardial infarction and permanent pacemaker implantation, were comparable between patients with DM and without DM. Insulin treated diabetics (n = 314) showed a trend to higher mortality compared with non-insulin treated diabetics (n = 701, Hazard Ratio 1.5, 95%CI 0.9–2.3, p = 0.08). EuroSCORE II was the most accurate risk score and underestimated 30-day mortality with an observed-expected ratio of 1.15 in DM patients, STS-PROM overestimated actual mortality with a ratio of 0.77 and Logistic EuroSCORE with 0.35. Conclusion: DM was not associated with mortality during the first year after TAVI. DM patients undergoing TAVI had low rates of mortality and other adverse clinical outcomes, comparable to non-DM TAVI patients. Our results underscore the safety of TAVI treatment in DM patients. Trial registration: The study is registered at clinicaltrials.gov (NCT03588247)

Balloon-expandable versus self-expandable valves in transcatheter aortic valve implantation: Complications and outcomes from a large international patient cohort

Background: Both balloon-expandable (BE) and self-expandable (SE) valves for tran-scatheter aortic valve implantation (TAVI) are broadly used in clinical practice. However, adequately powered randomized controlled trials comparing these two valve designs are lacking. Methods: The CENTER-study included 12,381 patients undergoing transfemoral TAVI. Patients undergoing TAVI with a BE-valve (n = 4096) were compared to patients undergoing TAVI with an SE-valve (n = 4096) after propensity score matching. Clinical outcomes including one-year mortality and stroke rates were assessed. Results: In the matched population of n = 5410 patients, the mean age was 81 ± 3 years, 60% was female, and the STS-PROM predicted 30-day mortality was 6.2% (IQR 4.0–12.4). One-year mortality was not different between patients treated with BE-or SE-valves (BE: 16.4% vs. SE: 17.0%, Relative Risk 1.04, 95%CI 0.02–1.21, p = 0.57). One-year stroke rates were also comparable (BE: 4.9% vs. SE: 5.3%, RR 1.09, 95%CI 0.86–1.37, p = 0.48). Conclusion: This study suggests that one-year mortality and stroke rates were comparable in patients with severe aortic valve stenosis undergoing TAVI with either BE or SE-valves

Impact of Mitral Regurgitation Etiology on Mitral Surgery After Transcatheter Edge-to-Edge Repair

International audienceBackground: Although >150,000 mitral TEER procedures have been performed worldwide, the impact of MR etiology on MV surgery after TEER remains unknown.Objectives: The authors sought to compare outcomes of mitral valve (MV) surgery after failed transcatheter edge-to-edge repair (TEER) stratified by mitral regurgitation (MR) etiology.Methods: Data from the CUTTING-EDGE registry were retrospectively analyzed. Surgeries were stratified by MR etiology: primary (PMR) and secondary (SMR). MVARC (Mitral Valve Academic Research Consortium) outcomes at 30 days and 1 year were evaluated. Median follow-up was 9.1 months (IQR: 1.1-25.8 months) after surgery.Results: From July 2009 to July 2020, 330 patients underwent MV surgery after TEER, of which 47% had PMR and 53.0% had SMR. Mean age was 73.8 ± 10.1 years, median STS risk at initial TEER was 4.0% (IQR: 2.2%-7.3%). Compared with PMR, SMR had a higher EuroSCORE, more comorbidities, lower LVEF pre-TEER and presurgery (all P < 0.05). SMR patients had more aborted TEER (25.7% vs 16.3%; P = 0.043), more surgery for mitral stenosis after TEER (19.4% vs 9.0%; P = 0.008), and fewer MV repairs (4.0% vs 11.0%; P = 0.019). Thirty-day mortality was numerically higher in SMR (20.4% vs 12.7%; P = 0.072), with an observed-to-expected ratio of 3.6 (95% CI: 1.9-5.3) overall, 2.6 (95% CI: 1.2-4.0) in PMR, and 4.6 (95% CI: 2.6-6.6) in SMR. SMR had significantly higher 1-year mortality (38.3% vs 23.2%; P = 0.019). On Kaplan-Meier analysis, the actuarial estimates of cumulative survival were significantly lower in SMR at 1 and 3 years.Conclusions: The risk of MV surgery after TEER is nontrivial, with higher mortality after surgery, especially in SMR patients. These findings provide valuable data for further research to improve these outcomes