Pulmonary hypertension and right ventricular dysfunction: prognostic implications in patients with different clinical phenotypes of ischemic heart failure. Summary of the doctoral thesis in medical sciences: 321.03 – Cardiology

Abstract

Heart failure (HF) is a heterogeneous syndrome with a poor prognosis. Its prevalence is 17.2 per 1000 individuals [1], varying between 1% - 3% of the adult population [2,3]. In terms of HF phenotype, the reported prevalence of HF with preserved ejection fraction (HFpEF) is continuously increasing, while the rate of HF with reduced ejection fraction (HFrEF) remains stable or gradually decreases [2]. Among the multiple causes of HF, coronary artery disease (CAD) represents the predominant etiology, accounting for 26% of the total burden [2,4]. The prognosis of HF has improved following the implementation of guideline-directed medical therapy. Nevertheless, the mortality rate remains elevated, ranging between 6.4% - 17.4% [2], while HF hospitalization accounts for approximately 1% – 2% of all-cause admissions, representing the leading cause of hospitalization among individuals aged over 65 years [4]. Although multiple scores for estimating mortality risk in HF are available, there are currently no reliable tools for assessing the risk of HF-related hospitalization or worsening HF (WHF) episodes [5], which are unfavourable outcomes with an enormous social and economic burden. The development of pulmonary hypertension (PH) represents a turning point in the natural course of HF [6], worsening its prognosis regardless of the HF phenotype. PH is further associated with an increased risk of both mortality [7–9] and morbidity [7,10]. The prevalence of PH associated with left heart disease (PH-LHD) varies between 36% - 83% in patients with HF [7,10]. The gold standard for the evaluation of pulmonary hemodynamics is right heart catheterization; however, as an invasive diagnostic method, it is often unjustified in subjects with LHD. Echocardiographic estimation of the PH probability (PHpr) is recommended in this category of patients, despite the fact that echocardiography has the capacity to both underestimate and overestimate pulmonary artery pressure [11]. PH-LHD can be stratified according to pulmonary vascular resistance (PVR) into isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH) [11,12]. Studies and meta-analyses have demonstrated a significant negative prognostic impact and reduced survival in patients with Cpc-PH [7,13]. Attempts have been made to identify non-invasive indicators that could estimate the presence of a precapillary component within PH-LHD [14,15]; however, their correlation with invasively measured parameters is not well demonstrated or validated, and their prognostic impact is supported by limited evidence. Despite being recognized in recent decades, the importance of right ventricular (RV) function and its prognostic role remains significantly underestimated. There is no unanimously accepted definition of right ventricular dysfunction (RVD). Thus, while some expert recommendations define it as the determination of a parameter that characterizes RV function outside the reference range [16], other sources emphasize the differentiation between RVD, which involves RV structural or functional abnormalities without hemodynamic compromise, and RV failure, caused by reduced filling and/or RV output [17,18]. The prevalence of RVD shows significant variability across studies and meta-analyses, ranging from 19% to 77%, due to the use of varying diagnostic criteria [21–24]. It is associated with a poor prognosis, independent of the underlying pathogenetic mechanism: throughout the entire spectrum of HF phenotypes [18,21,22], after cardiac surgery [23], acute myocardial infarction (AMI) [24] and PH [11]. Surgical or percutaneous myocardial revascularization has made remarkable progress in managing obstructive CAD. Percutaneous coronary intervention (PCI) has a clear benefit in improving survival in patients with AMI [25], while coronary artery bypass grafting (CABG) has proven effective in reducing cardiovascular (CV) mortality and hospitalization over a 10-year period in patients with severe left ventricular (LV) systolic dysfunction [26]. However, studies comparing the outcomes of patients undergoing CABG [26] or PCI [25,27] with optimal medical therapy, as well as those evaluating the two types of myocardial revascularization [28,29], have primarily focused on endpoints such as mortality, CV-related hospitalization, and the risk of AMI or stroke. Limited studies have explored the long-term evolution of ischemic HF and its phenotypes, so the impact of myocardial revascularization on HF prognosis remains insufficiently elucidated. Although some small studies have analyzed RV function or PH in patients undergoing CABG or PCI, these have primarily focused on the early postoperative stage, as well as their shortterm prognostic impact. Thus, the prevalence, evolution and long-term prognostic value of PH and RVD in patients who have undergone myocardial revascularization through CABG or PCI are sparsely and fragmentarily reported in the specialized literature. The aim of this study was to investigate the characteristics of pulmonary hypertension associated with left heart disease and right ventricular dysfunction in patients with ischemic heart failure, as well as to develop long-term prognostic criteria following myocardial revascularization. The objectives of the research were: 1. To assess the evolution of manifestations defining heart failure phenotypes over 12 months after myocardial revascularization. 2. To analyze the evolution of echocardiographic parameters suggestive of postcapillary pulmonary hypertension and its subtypes 12 months following myocardial revascularization, and to investigate their correlation with heart failure phenotypes 3. To estimate the modifications of right ventricular function parameters over 12 months after myocardial revascularization. 4. To perform a comparative analysis of the evolution of pulmonary hypertension, right and left ventricular dysfunction according to the type of myocardial revascularization: coronary artery bypass grafting or percutaneous coronary intervention. 5. To develop long-term prognostic criteria for the evolution of ischemic heart failure after myocardial revascularization and to determine the impact of pulmonary hypertension and right ventricular dysfunction in this context. Scientific novelty and originality. The research provided new data on the prevalence of PH in patients with ischemic HF and myocardial revascularization. For the first time in the Republic of Moldova, we performed non-invasive (echocardiographic) diagnosis of postcapillary PH subtypes (IpcPH and CpcPH), with estimation of their prevalence in patients undergoing myocardial revascularization. We established a moderate and statistically significant correlation between echocardiographic parameters defining PH and HF characteristics. The independent impact of the HFrEF phenotype, LV remodeling and diastolic dysfunction parameters, the preexisting early changes within the pulmonary circulation, CV and non-CV comorbidities (arterial hypertension, atrial fibrillation, chronic kidney disease) on the progression of the echocardiographic probability of PH was demonstrated. Furthermore, we reported the prevalence of RVD in patients with both surgical and percutaneous myocardial revascularization, thus supplementing the existing data in this field. We presented evidence supporting a multifactorial pathophysiological mechanism in the development of RVD in patients with ischemic HF, determined by ventricular interdependence, RV afterload and the impaired RV- pulmonary artery coupling. For the first time in the Republic of Moldova, the cardiopulmonary exercise test (CPET) was conducted in patients with PH and RVD, demonstrating reduced peak oxygen uptake (VO2p) and ventilatory inefficiency. As a result of this study, we provided solid evidence of the major prognostic impact of echocardiographic parameters defining PH and RVD on the risk of HF hospitalization and WHF episodes, as well as on the composite endpoint of all-cause mortality and HF-related hospitalization. The scientific issue addressed in the research consists in identifying the parameters of PH and RVD with prognostic impact and quantifying their contribution in patients with ischemic HF and myocardial revascularization with respect to the defined endpoints – HF hospitalization and WHF episodes, as well as the composite endpoint: all-cause mortality and HF hospitalization. Additionally, prognostic factors determining the progression of the echocardiographic probability of PH at 12 months after the acute cardiac event were identified, thereby revealing the impact of both systolic and diastolic LV dysfunction, early changes in the pulmonary vascular bed and of CV and non-CV comorbidities in the development of PH-LHD. At the same time, prognostic determinants influencing de novo RVD at 12 months after myocardial revascularization were highlighted, emphasizing the importance of RV afterload, RV–pulmonary artery coupling and ventricular interdependence. The theoretical significance of the research lies in identifying the correlation between PH-LHD, its subtypes and HF phenotypes in patients who underwent myocardial revascularization through CABG or PCI. Additionally, the parameters that demonstrated prognostic impact in the context of progression of the echocardiographic probability of PH 12 months after myocardial revascularization suggest the presence of subtle alterations in pulmonary circulation early after the acute cardiac event. These changes appear to progress under the influence of systolic and diastolic LV dysfunction, interacting with CV comorbidities (arterial hypertension and atrial fibrillation) and non-CV comorbidities (chronic kidney disease). At the same time, the impact of LV morphofunctional characteristics, echocardiographic parameters of PH and its precapillary component on the development of de novo RVD outlines a multifactorial pathophysiological mechanism underlying RVD in patients undergoing myocardial revascularization: ventricular interdependence and increased afterload, with impaired RV–pulmonary artery coupling. Strong arguments were presented in support of the major determining role of PH and RVD in the progression of ischemic HF, enhancing the risk of all-cause mortality, HF-related hospitalization and WHF. Practical value of the research. The study demonstrated the feasibility of non-invasive echocardiographic differentiation of PH-LHD subtypes: IpcPH and CpcPH. The research emphasized the importance of incorporating parameters characterizing RV morphology and systolic function, as well as PH indices, such as tricuspid regurgitation velocity (TRV) and additional signs suggestive of PH, into the echocardiographic protocol for the follow up examination of patients who underwent CABG or PCI. These parameters have proven to be prognostic determinants in the evolution of HF. Furthermore, the study highlighted the relevance of integrating CPET into the evaluation protocol for patients who underwent myocardial revascularization, both for characterization the evolution of exercise capacity and for the assessment of gas exchange parameters with prognostic significance in this patient population. As a result of the conducted study, five prognostic methods were developed. Two prediction models estimate the risk of HF-related hospitalization during the first year after myocardial revascularization. Given the negative prognostic impact of WHF, we developed the prognostic method for evaluation the risk of WHF during the first year after myocardial revascularization. Additionally, predictive models were created for assessing the risk of unfavourable evolution of PH and RVD. Publications related to the thesis topic. The findings of the study have been reflected in 26 publications, including 1 article in a journal with an impact factor of 16.9, 2 articles in SCOPUS – indexed journals where the author is the first author, 5 articles in category B journals, 3 articles in category C journals, 11 abstracts in the proceedings of international scientific congresses and 4 theses in the proceedings of national scientific conferences. Approval of Scientific Results. The relevant results derived from this research have been presented and discussed at numerous scientific forums, including: the Heart Failure Congress (2020 – online, May 21-24, 2022 in Madrid, Spain; May 20-23, 2023 in Prague, Czech Republic; May 11-14, 2024 in Lisbon, Portugal), ESC Preventive Cardiology Congress (2020 and 2022, online), the National Cardiology Congress (September 21-24, 2022 in Sinaia, Romania); as well as national conferences: the Annual Scientific Conference of USMF “N. Testemițanu” (2021 and 2022 in Chișinău), the scientific conference marking World COPD Day (November 22, 2019, Chișinău), the scientific conference “Pulmonary Hypertension in Daily Clinical Practice” (October 7, 2023, Chișinău) and the Scientific Conference within the International Specialized Exhibition “MoldMedizin & MoldDent” (September 27, 2024, Chișinău). The results of the thesis were discussed and approved during the meeting of the Chronic Heart Failure Laboratory of the Institute of Cardiology (no. 3 of 27.03.2025) and the Specialized Scientific Seminar 321.03–Cardiology, 321.23–Cardiac Surgery (no. 2 of 02.05.2025).