Advanced diagnostics and novel therapeutic strategies in ischemic heart disease

Abstract

Ischemic heart disease remains the leading cause of morbidity and premature mortality worldwide. The incidence of acute myocardial infarction (AMI) is expected to rise in the coming years. Combined with improved survival rates following AMI due to advances in treatment, this will likely lead to an increase in the number of patients with ischemic heart failure. Ischemic damage to the heart is characterized by the replacement of functional myocardium with fibrosis, a key prognostic factor for mortality and heart failure development. To date, myocardial regeneration as a curative therapy is not feasible. Part 1 – Advanced Diagnostics in Ischemic Heart Disease Identifying patients who may benefit from intensive antifibrotic medication or aggressive reperfusion therapy remains a clinical challenge. Currently, biomarkers (e.g., creatine kinase and troponin) and imaging are used to assess post-infarction damage, with left ventricular ejection fraction (LVEF) being the most commonly utilized parameter. However, LVEF may not accurately assess regional damage as seen in infarction and can be affected by compensatory mechanisms, leading to underestimation or overestimation of the extent of damage. Chapter 2 investigates two-dimensional speckle-tracking echocardiography (2D-STE) for assessing myocardial strain post-infarction, comparing its performance against LVEF and wall motion analysis, using late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR) as the reference standard. We found that segmental strain analysis could predict the presence of non-infarcted, subendocardial, and transmural scars, although global strain in the post-acute phase did not outperform conventional echocardiographic parameters. Chapter 3 explores myocardial work, a novel 2D-STE-based technique that derives preload-independent myocardial function parameters. The study demonstrated that global work parameters improved over time post-infarction and could distinguish non-scarred from transmural infarcted segments. However, the technique did not surpass conventional strain analysis in diagnostic accuracy. In Chapter 4, the role of circulating biomarkers of collagen homeostasis, specifically PICP and ICTP, in scar formation post-infarction was examined. While both biomarkers showed temporal changes post-infarction, their correlation with infarct size was weak, limiting their clinical utility compared to traditional biomarkers. Part 2 – Advanced Imaging in New Treatments for Ischemic Heart Failure Although myocardial regeneration has never been established clinically, many studies have shown a possible improvement of heart function after cell based therapies. However, recent studies have questioned the efficacy and relevance of cell therapy in improving cardiac function. Chapter 5 systematically reviews the application of strain analysis in cardiac regenerative therapy research. Strain parameters may be superior over conventional echocardiography in detecting the possible subtle regional effects of cell based therapies. Chapters 6 and 7 discuss the SCIENCE trial, which assessed the safety and efficacy of allogeneic mesenchymal stromal cell therapy in ischemic heart failure. The trial found no significant improvement in primary or secondary endpoints, casting doubt on the clinical relevance of such therapies. In conclusion, this thesis highlights the potential of strain analysis in both diagnostics after myocardial infarctin and evaluation of cell based therapies for ischemic heart disease, but underscores the limitations of current cell therapy approaches. Future research should focus on alternative strategies for clinically relevant cardiac repair.