Biomarkers for Predicting Atherosclerotic Vascular Disease and Heart Failure Progression

Cardiovascular disease represents a complex continuum of interconnected pathophysiological processes involving the vascular system, the heart, and systemic metabolic and inflammatory pathways. Traditionally, cardiovascular conditions have been studied and managed as distinct entities—atherosclerosis, valvular heart disease, heart failure, and pulmonary vascular disease. However, growing evidence suggests that these conditions frequently coexist and evolve along a shared biological trajectory characterized by vascular ageing, cardiometabolic dysregulation, structural cardiac remodelling, and progressive haemodynamic impairment. Within this framework, the concept of cardiovascular phenotyping has emerged as a central paradigm in contemporary cardiovascular research.4 Rather than focusing on isolated disease categories, this approach aims to identify measurable biological signals—commonly referred to as biomarkers—that capture the multidimensional processes underlying disease progression. These biomarkers may derive from circulating molecules, imaging findings, haemodynamic measurements, or functional testing, and increasingly reflect the integration of multiple physiological domains. Among the available tools, cardiovascular imaging plays a pivotal role in modern biomarker discovery. Echocardiography, stress imaging and multimodal ultrasound-based techniques allow non-invasive characterization of structural remodelling, haemodynamic adaptation, and systemic congestion.6 When combined with laboratory markers and clinical phenotyping, these techniques provide a unique opportunity to investigate how local cardiac abnormalities interact with systemic metabolic and inflammatory states to determine disease expression and prognosis. The research work presented in this thesis was developed within this conceptual framework and focuses on the identification and interpretation of imaging-derived and physiological biomarkers across the spectrum of cardiovascular disease, from vascular pathology to advanced heart failure. Rather than addressing a single disease entity, the studies included in this section explore how specific biomarkers reflect different stages of cardiovascular dysfunction and may help refine risk stratification, mechanistic understanding, and clinical decision-making. The first group of studies presented in this thesis (Atherosclerotic Vascular Disease and Aortic Stenosis) explores the relationship between systemic atherosclerotic vascular disease and degenerative aortic valve disease, with a particular focus on imaging and clinical biomarkers capable of capturing this interaction. Degenerative aortic stenosis frequently develops in patients with a high burden of cardiometabolic risk factors and often coexists with atherosclerotic disease involving coronary, carotid, and peripheral arterial territories. This overlap suggests that valvular degeneration may represent, at least in part, a manifestation of systemic vascular ageing rather than an isolated valvular disorder.3,8 However, the mechanisms linking systemic vascular pathology to the phenotypic expression of aortic valve disease remain incompletely understood. The studies included in this section address this relationship from complementary perspectives. The first investigation evaluates the role of cardiometabolic and imaging biomarkers—including epicardial adipose tissue and markers of cardiac structural remodelling—in shaping the severity of aortic stenosis across different stages of disease. By integrating patients with systemic atherosclerotic disease and those with established valvular pathology, this work aims to disentangle the contribution of systemic vascular risk from the mechanisms specifically driving valvular degeneration. The second study examines the clinical implications of systemic vascular disease in patients undergoing transcatheter aortic valve replacement (TAVR). In particular, it investigates the prediction of peri-procedural cerebrovascular complications in patients with severe peripheral artery disease using integrated clinical and anatomical risk scores derived from the HOSTILE registry. This analysis highlights how the burden of peripheral atherosclerosis influences procedural risk and illustrates the broader impact of systemic vascular pathology on the outcomes of valvular interventions. Taken together, these studies illustrate how systemic vascular disease may influence both the development of aortic valve pathology and the risk profile of its interventional treatment, underscoring the importance of integrated cardiovascular phenotyping in patients with valvular heart disease. The second research line (Heart Failure and Pulmonary Hypertension) investigates the haemodynamic and functional determinants of pulmonary congestion in heart failure, with particular focus on the role of right ventricular–pulmonary arterial coupling during exercise. In patients with heart failure, resting haemodynamic measurements often underestimate the complexity of cardiovascular dysfunction. Exercise stress echocardiography combined with cardiopulmonary testing and lung ultrasound allows the assessment of dynamic physiological responses that better reflect the mechanisms underlying symptoms and exercise intolerance.6 The study included in this section examines how alterations in right ventricular adaptation to pulmonary vascular load contribute to the development of exercise-induced pulmonary congestion. This observation challenges the traditional assumption that right ventricular dysfunction necessarily limits pulmonary congestion by reducing forward flow. Instead, impaired right ventricular–pulmonary arterial coupling during exercise may favour increases in left ventricular filling pressures and the development of dynamic pulmonary congestion. Finally, the third group of studies (Mitral Valve Disease and Tricuspid Regurgitation) focuses on advanced heart failure and right-sided heart disease, particularly secondary mitral regurgitation and tricuspid regurgitation, conditions in which circulatory dysfunction reflects complex interactions between ventricular performance, systemic congestion, and metabolic-inflammatory activation. The first investigation evaluates patients with secondary mitral regurgitation undergoing transcatheter edge-to-edge repair and demonstrates that right ventricular impairment represents a key determinant of prognosis. In this setting, adherence to guideline-directed medical therapy for heart failure significantly influences long-term survival, highlighting the interplay between valvular pathology, right ventricular function, and systemic heart failure management. A second study explores the haemodynamic and biological heterogeneity of moderate-to-severe tricuspid regurgitation by integrating echocardiographic assessment with metabolic and inflammatory profiling. Stratification according to cardiac index revealed distinct circulatory phenotypes ranging from hypodynamic states characterized by impaired forward flow and right ventricular–pulmonary arterial uncoupling to hyperdynamic profiles associated with systemic congestion, inflammatory activation, and metabolic derangements. This work demonstrates that both low and high cardiac output states identify high-risk patients and that intermediate flow conditions are associated with more favorable outcomes. Together, these studies reflect a common research trajectory centred on the integrative characterization of cardiovascular disease using multimodal biomarkers, with particular emphasis on the role of cardiovascular imaging in bridging mechanistic insights and clinical practice. By combining imaging-derived parameters with haemodynamic, metabolic, and inflammatory biomarkers, this approach allows a more comprehensive characterization of disease phenotypes that extend beyond traditional anatomical classifications. Such integrative phenotyping may help identify distinct pathophysiological profiles, refine risk stratification, and ultimately support more individualized therapeutic strategies. In this perspective, multimodal biomarker assessment has the potential to contribute to the transition from a disease-centred to a patient-centred approach in cardiovascular medicine, enabling more precise selection and timing of therapeutic interventions.