Paolisso, Pasquale (2023) Contemporary challenges in diagnosis, risk stratification, and management of patients with clinically significant aortic stenosis. [Tesi di dottorato]

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Abstract

In this thesis, we report the main findings of our research projects about the diagnosis, risk stratification, and management of patients with AS, with a particular focus on recent developments and future directions. Starting from pathophysiology, recently, there has been a first clear shift from the paradigm of passive “wear and tear” to consider AS as a metabolically “active, highly regulated, and potentially modifiable” disease process, with both an initiation and progression phase, sharing several similarities with atherosclerosis. Biological markers enabling early detection of focal fibrosis or monitoring the natural history of AS are highly warranted to improve risk stratification, determine optimal timing for aortic valve replacement (AVR), and anticipate the potential futility of the treatment strategy adopted. Blood and tissue biomarkers have a differential pattern and expression level in patients with AS, which may retain a pathophysiological role in cardiac remodeling and metabolism. However, data available are limited and contradictory. The relationship between markers of cardiac remodeling, fibrosis, inflammation, oxidative stress, and cardiac metabolism remains unexplored. The second paradigm shift concerns the conception of AS as a pathology of both the valve and myocardium rather than an isolated pathology of the aortic valvular apparatus. In this perspective, besides grading AS severity, the assessment of the extravalvular cardiac damage appears to be crucial for risk stratification and prognosis of patients with AS. In the diagnostic work-up of patients with AS, echocardiography remains the reference standard; however, other imaging modalities are now increasingly being used, providing complementary information to guide clinical decision-making. Indeed, the myocardial remodeling response to AS varies among individuals and has an important influence on the development of symptoms, heart failure (HF), and long-term prognosis. AS causes an increase in the afterload, triggering a hypertrophic remodeling response that restores wall stress and cardiac performance for many years in accordance with the law of Laplace. Importantly, the degree of left ventricular (LV) hypertrophy is not well predicted by AS severity alone, being influcenced by multiple other factors (i.e. arterial hypertension, sex, and genetic polymorphisms), driving the patients' transition to adverse clinical events. Other echocardiographic techniques are emerging to provide more sensitive assessments of LV function in AS. In particular, speckle-tracking echocardiography with global longitudinal strain is a more sensitive marker of systolic dysfunction than ejection fraction. Assessment of left atrial dilatation, pulmonary artery pressure, right ventricular dysfunction, and tricuspid regurgitation provides additional information on the stage of disease and may impact the prognosis of patients with AS. On this basis, a classification for staging the extent of “extravalvular” cardiac damage has recently been proposed, integrating progressive involvement of the chambers of the heart. The cardiac damage staging may also be useful in selecting the optimal type and timing of AVR, either surgical or transcatheter (SAVR/TAVR). Careful consideration should be given to whether the cardiac chamber remodeling is due to AS or other co-morbidities (e.g. pulmonary hypertension or right ventricular dysfunction) and, thus, whether improvement could be expected after AVR. The third paradigm shift consists in the spread of III-level specialized centers for the management and treatment of patients with AS. Indeed, recently, an increasing number of patients with VHD is being managed in Heart Valve Clinics (HVCs), which offer multidisciplinary services and fast and easy referral to other necessary disciplines, enhancing the quality of patient care (15). According to the ESC/AHA Guidelines, the HVCs include: i) availability of the entire spectrum of surgical and transcatheter valve procedures with 24/7 services, ii) weekly Heart Team meetings; iii) organization of a HVC for ambulatory management; iv) use of multimodality imaging including echocardiography, cardiac CT, cardiac magnetic resonance and nuclear medicine, v) yearly evaluation of patients outcomes with quality check and planning of educational programs. The HVC involves cardiologists with expertise in VHD, cardiac imaging specialists, cardio-anesthesiologists, cardiac surgeons, and dedicated nurses. The last part of this thesis is dedicated to the role of coronary microvascular dysfunction in the natural history of AS. Severe AS is associated with variable impact on LV remodeling and coronary flow regulation. Development of left ventricular hypertrophy in patients with AS is an adaptive response aimed at increasing contractile forces and reducing wall stress in LV to eventually maintain a preserved stroke volume for many years despite an elevated LV afterload. In this setting, a series of unfavorable hemodynamic changes, including high LV cavity pressure, low coronary perfusion pressure, and increased extravascular compressive forces, lead to a flow shift from the endocardium to the epicardium, resulting in subendocardial ischemia, despite the absence of significant obstructive coronary artery disease. In addition, the progression of LV hypertrophy increases myocardial oxygen demand, resulting in a supply-demand mismatch, which requires an increase of the resting coronary flow due to the vasodilation of intramyocardial arterioles induced by the autoregulation phenomenon. On the clinical ground, as a result of the LV oxygen supply-demand mismatch, exercise/tachycardia-induced myocardial ischemia and exertional angina might occur in patients with severe AS. However, the interplay among coronary flow, microvascular regulation, severity of AS, LV hypertrophy, and hemodynamic overload remains complex, multifactorial, and poorly understood.

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