The Biological Bases of Group 2 Pulmonary Hypertension

Pulmonary hypertension (PH) is a potentially fatal condition with a prevalence of around 1% in the world population and most commonly caused by left heart disease (PH-LHD). Usually, in PH-LHD, the increase of pulmonary pressure is only conditioned by the retrograde transmission of the left atrial pressure. However, in some cases, the long-term retrograde pressure overload may trigger complex and irreversible biomechanical and biological changes in the pulmonary vasculature. This latter clinical entity, designated as combined pre- and post-capillary PH, is associated with very poor outcomes. The underlying mechanisms of this progression are poorly understood, and most of the current knowledge comes from the field of Group 1-PAH. Treatment is also an unsolved issue in patients with PH-LHD. Targeting the molecular pathways that regulate pulmonary hemodynamics and vascular remodeling has provided excellent results in other forms of PH but has a neutral or detrimental result in patients with PH-LHD. Therefore, a deep and comprehensive biological characterization of PH-LHD is essential to improve the diagnostic and prognostic evaluation of patients and, eventually, identify new therapeutic targets. Ongoing research is aimed at identify candidate genes, variants, non-coding RNAs, and other biomarkers with potential diagnostic and therapeutic implications. In this review, we discuss the state-of-the-art cellular, molecular, genetic, and epigenetic mechanisms potentially involved in PH-LHD. Signaling and effective pathways are particularly emphasized, as well as the current knowledge on -omic biomarkers. Our final aim is to provide readers with the biological foundations on which to ground both clinical and pre-clinical research in the field of PH-LHD

Ramipril in High-Risk Patients With COVID-19.

Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory-syndrome coronavirus-2 that interfaces with the renin-angiotensin-aldosterone system (RAAS) through angiotensin-converting enzyme 2. This interaction has been proposed as a potential risk factor in patients treated with RAAS inhibitors. This study analyzed whether RAAS inhibitors modify the risk for COVID-19. The RASTAVI (Renin-Angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation) trial is an ongoing randomized clinical trial randomly allocating subjects to ramipril or control groups after successful transcatheter aortic valve replacement at 14 centers in Spain. A non-pre-specified interim analysis was performed to evaluate ramipril's impact on COVID-19 risk in this vulnerable population. As of April 1, 2020, 102 patients (50 in the ramipril group and 52 in the control group) were included in the trial. Mean age was 82.3 ± 6.1 years, 56.9% of the participants were male. Median time of ramipril treatment was 6 months (interquartile range: 2.9 to 11.4 months). Eleven patients (10.8%) have been diagnosed with COVID-19 (6 in control group and 5 receiving ramipril; hazard ratio: 1.150; 95% confidence interval: 0.351 to 3.768). The risk of COVID-19 was increased in older patients (p = 0.019) and those with atrial fibrillation (p = 0.066), lower hematocrit (p = 0.084), and more comorbidities according to Society of Thoracic Surgeons score (p = 0.065). Admission and oxygen supply was required in 4.9% of patients (2 in the ramipril group and 3 in the control group), and 4 of them died (2 in each randomized group). A higher body mass index was the only factor increasing the mortality rate (p = 0.039). In a high-risk population of older patients with cardiovascular disease, randomization to ramipril had no impact on the incidence or severity of COVID-19. This analysis supports the maintenance of RAAS inhibitor treatment during the COVID-19 crisis. (Renin-Angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation [RASTAVI]; NCT03201185).This project was granted by the Insituto de Salud Carlos III (Madrid, Spain) (PI17/02237).S

Mitral Regurgitation After Transcatheter Aortic Valve Replacement: Prognosis, Imaging Predictors, and Potential Management.

This study sought to analyze the clinical impact of the degree and improvement of mitral regurgitation in TAVR recipients, validate the main imaging determinants of this improvement, and assess the potential candidates for double valve repair with percutaneous techniques. Many patients with severe aortic stenosis present with concomitant mitral regurgitation (MR). Cardiac imaging plays a key role in identifying prognostic factors of MR persistence after transcatheter aortic valve replacement (TAVR) and for planning its treatment. A total of 1,110 patients with severe aortic stenosis from 6 centers who underwent TAVR were included. In-hospital to 6-month follow-up clinical outcomes according to the degree of baseline MR were evaluated. Off-line analysis of echocardiographic and multidetector computed tomography images was performed to determine predictors of improvement, clinical outcomes, and potential percutaneous alternatives to treat persistent MR. Compared with patients without significant pre-TAVR MR, 177 patients (16%) presented with significant pre-TAVR MR, experiencing a 3-fold increase in 6-month mortality (35.0% vs. 10.2%; p 35.5 mm (odds ratio: 9.0; 95% confidence interval: 3.2 to 25.3; p  Significant MR is not uncommon in TAVR recipients and associates with greater mortality. In more than one-half of patients, the degree of MR improves after TAVR, which can be predicted by characterizing the mitral apparatus with multidetector computed tomography. According to standardized imaging criteria, at least 1 in 10 patients whose MR persists after TAVR could benefit from percutaneous mitral procedures, and even more could be treated with MitraClip after dedicated pre-imaging evaluation

Infective Endocarditis Following Transcatheter Aortic Valve Replacement:Comparison of Balloon-Versus Self-Expandable Valves

No data exist about the characteristics of infective endocarditis (IE) post-transcatheter aortic valve replacement (TAVR) according to transcatheter valve type. We aimed to determine the incidence, clinical characteristics, and outcomes of patients with IE post-TAVR treated with balloon-expandable valve (BEV) versus self-expanding valve (SEV) systems. Data from the multicenter Infectious Endocarditis After TAVR International Registry was used to compare IE patients with BEV versus SEV. A total of 245 patients with IE post-TAVR were included (SEV, 47%; BEV, 53%). The timing between TAVR and IE was similar between groups (SEV, 5.5 [1.2-15] months versus BEV, 5.3 [1.7-11.4] months; P=0.89). Enterococcal IE was more frequent in the SEV group (36.5% versus 15.4%; P The characteristics of IE post-TAVR, including microorganism type, vegetation location, and embolic complications but not early or late mortality, differed according to valve type. These results may help to guide the diagnosis and management of IE and inform future research studies in the field

Temporal Trends, Characteristics, and Outcomes of Infective Endocarditis After Transcatheter Aortic Valve Replacement.

Procedural improvements combined with the contemporary clinical profile of patients undergoing transcatheter aortic valve replacement (TAVR) may have influenced the incidence and outcomes of infective endocarditis (IE) following TAVR. We aimed to determine the temporal trends, characteristics, and outcomes of IE post-TAVR. Observational study including 552 patients presenting definite IE post-TAVR. Patients were divided in 2 groups according to the timing of TAVR (historical cohort [HC]: before 2014; contemporary cohort [CC]: after 2014). Overall incidence rates of IE were similar in both cohorts (CC vs HC: 5.45 vs 6.52 per 1000 person-years; P = .12), but the rate of early IE was lower in the CC (2.29‰ vs 4.89‰, P < .001). Enterococci were the most frequent microorganism. Most patients presented complicated IE ( CC: 67.7%; HC: 69.6%; P = .66), but the rate of surgical treatment remained low (CC: 20.7%; HC: 17.3%; P = .32). The CC exhibited lower rates of in-hospital acute kidney injury (35.1% vs 44.6%; P = .036) and in-hospital (26.6% vs 36.4%; P = .016) and 1-year (37.8% vs 53.5%; P < .001) mortality. Higher logistic EuroScore, Staphylococcus aureus etiology, and complications (stroke, heart failure, and acute renal failure) were associated with in-hospital mortality in multivariable analyses (P < .05 for all). Although overall IE incidence has remained stable, the incidence of early IE has declined in recent years. The microorganism, high rate of complications, and very low rate of surgical treatment remained similar. In-hospital and 1-year mortality rates were high but progressively decreased over time

Mitral Valve Infective Endocarditis after Trans-Catheter Aortic Valve Implantation.

Scarce data exist on mitral valve (MV) infective endocarditis (IE) after transcatheter aortic valve implantation (TAVI). This multicenter study included a total of 579 patients with a diagnosis of definite IE after TAVI from the IE after TAVI International Registry and aimed to evaluate the incidence, characteristics, management, and outcomes of MV-IE after TAVI. A total of 86 patients (14.9%) had MV-IE. These patients were compared with 284 patients (49.1%) with involvement of the transcatheter heart valve (THV) only. Two factors were found to be associated with MV-IE: the use of self-expanding valves (adjusted odds ratio 2.49, 95% confidence interval [CI] 1.23 to 5.07, p = 0.012), and the presence of an aortic regurgitation ≥2 at discharge (adjusted odds ratio 3.33; 95% CI 1.43 to 7.73, p <0.01). There were no differences in IE timing and causative microorganisms between groups, but surgical management was significantly lower in patients with MV-IE (6.0%, vs 21.6% in patients with THV-IE, p = 0.001). All-cause mortality rates at 2-year follow-up were high and similar between patients with MV-IE (51.4%, 95% CI 39.8 to 64.1) and patients with THV-IE (51.5%, 95% CI 45.4 to 58.0) (log-rank p = 0.295). The factors independently associated with increased mortality risk in patients with MV-IE were the occurrence of heart failure (adjusted p <0.001) and septic shock (adjusted p <0.01) during the index hospitalization. One of 6 IE episodes after TAVI is localized on the MV. The implantation of a self-expanding THV and the presence of an aortic regurgitation ≥2 at discharge were associated with MV-IE. Patients with MV-IE were rarely operated on and had a poor prognosis at 2-year follow-up

Perivalvular Extension of Infective Endocarditis after Transcatheter Aortic Valve Replacement.

BACKGROUND Infective endocarditis (IE) following transcatheter aortic valve replacement (TAVR) has been associated with a dismal prognosis. However, scarce data exist on IE perivalvular extension (PEE) in such patients. METHODS This multicenter study included a total of 579 patients who had the diagnosis of definite IE at a median of 171 (53-421) days following TAVR. PEE was defined as the presence of an intracardiac abscess, pseudoaneurysm or fistula confirmed by transthoracic/transophageal echocardiography, computed tomography or peri-operative findings. RESULTS A total of 105 patients (18.1%) were diagnosed with PEE (perivalvular abscess, pseudoaneurysm, fistula, or a combination in 87, 7, 7, and 4 patients, respectively). A history of chronic kidney disease (ORadj: 2.08; 95% CI: [1.27-3.41], p=0.003) and IE secondary to coagulase-negative staphylococci (ORadj: 2.71; 95% CI: [1.57-4.69], p<0.001) was associated with an increased risk of PEE. Surgery was performed at index IE episode in 34 patients (32.4%) with PEE (vs. 15.2% in patients without PEE, p<0.001). In-hospital and 2-year mortality rates among PEE-IE patients were 36.5% and 69.4%, respectively. Factors independently associated with an increased mortality risk were the occurrence of other complications (stroke post-TAVR, acute renal failure, septic shock) and the lack of surgery at index IE hospitalization (padj<0.05 for all). CONCLUSION PEE occurred in about one fifth of IE post-TAVR patients, with the presence of coagulase-negative staphylococci and chronic kidney disease determining an increased risk. Patients with PEE-IE exhibited very high early and late mortality rates, and surgery during IE hospitalization seemed to be associated with better outcomes

Infective Endocarditis Caused by Staphylococcus aureus After Transcatheter Aortic Valve Replacement.

BACKGROUND Staphylococcus aureus (SA) has been extensively studied as causative microorganism of surgical prosthetic-valve infective endocarditis (IE). However, scarce evidence exists on SA IE after transcatheter aortic valve replacement (TAVR). METHODS Data were obtained from the Infectious Endocarditis After TAVR International Registry, including patients with definite IE after TAVR from 59 centres in 11 countries. Patients were divided into 2 groups according to microbiologic etiology: non-SA IE vs SA IE. RESULTS SA IE was identified in 141 patients out of 573 (24.6%), methicillin-sensitive S aureus in most cases (115/141, 81.6%). Self-expanding valves were more common than balloon-expandable valves in patients with early SA IE. Major bleeding and sepsis complicating TAVR, neurologic symptoms or systemic embolism at admission, and IE with cardiac device involvement other than the TAVR prosthesis were associated with SA IE (P < 0.05 for all). Among post-TAVR patients with IE, the likelihood of SA IE increased from 19% in the absence of those risk factors to 84.6% if ≥ 3 risk factors were present. In-hospital (47.8% vs 26.9%; P < 0.001) and 2-year (71.5% vs 49.6%; P < 0.001) mortality rates were higher among patients with SA IE vs non-SA IE. Surgery at the time of index SA IE was associated with a lower mortality rate at follow-up (adjusted hazard ratio 0.46, 95% CI 0.22-0.96; P = 0.038). CONCLUSIONS SA IE represented approximately 25% of IE cases after TAVR and was associated with very high in-hospital and late mortality. The presence of some features determined a higher likelihood of SA IE and could help to orientate early antibiotic regimen selection. Surgery at index SA IE was associated with improved outcomes, and its role should be evaluated in future studies

Surgical Treatment of Patients With Infective Endocarditis After Transcatheter Aortic Valve Implantation

International audienceBackground: The optimal treatment of patients developing infective endocarditis (IE) after transcatheter aortic valve implantation (TAVI) is uncertain.Objectives: The goal of this study was to investigate the clinical characteristics and outcomes of patients with TAVI-IE treated with cardiac surgery and antibiotics (IE-CS) compared with patients treated with antibiotics alone (IE-AB).Methods: Crude and inverse probability of treatment weighting analyses were applied for the treatment effect of cardiac surgery vs medical therapy on 1-year all-cause mortality in patients with definite TAVI-IE. The study used data from the Infectious Endocarditis after TAVI International Registry.Results: Among 584 patients, 111 patients (19%) were treated with IE-CS and 473 patients (81%) with IE-AB. Compared with IE-AB, IE-CS was not associated with a lower in-hospital mortality (HRunadj: 0.85; 95% CI: 0.58-1.25) and 1-year all-cause mortality (HRunadj: 0.88; 95% CI: 0.64-1.22) in the crude cohort. After adjusting for selection and immortal time bias, IE-CS compared with IE-AB was also not associated with lower mortality rates for in-hospital mortality (HRadj: 0.92; 95% CI: 0.80-1.05) and 1-year all-cause mortality (HRadj: 0.95; 95% CI: 0.84-1.07). Results remained similar when patients with and without TAVI prosthesis involvement were analyzed separately. Predictors for in-hospital and 1-year all-cause mortality included logistic EuroSCORE I, Staphylococcus aureus, acute renal failure, persistent bacteremia, and septic shock.Conclusions: In this registry, the majority of patients with TAVI-IE were treated with antibiotics alone. Cardiac surgery was not associated with an improved all-cause in-hospital or 1-year mortality. The high mortality of patients with TAVI-IE was strongly linked to patients' characteristics, pathogen, and IE-related complications