Conduction system pacing: how far are we from the "electrical" bypass?

Conduction system pacing is an alternative practice to conventional right ventricular apical pacing. It is a method that maintains physiologic ventricular activation, based on a correct pathophysiological basis, in which the pacing lead bypasses the lesion of the electrical fibers and the electrical impulse transmits through the intact adjacent conduction system. For this reason, it might be reasonably characterized by the term "electrical bypass" compared to the coronary artery bypass in revascularization therapy. In this review, reference is made to the sequence of events in which conventional right ventricular pacing may cause adverse outcomes. Furthermore, there is a reference to alternative strategies and pacing sites. Interest focuses on the modalities for which there are data from the literature, namely for the right ventricular (RV) septal pacing, the His bundle pacing (HBP), and the left bundle branch pacing (LBBP). A more extensive reference is about the HBP, for which there are the most updated data. We analyze the considerations that limit HBP-wide application in three axes, and we also present the data for the implantation and follow-up of these patients. The indications with their most important studies to date are then described in detail, not only in their undoubtedly positive findings but also in their weak aspects, because of which this pacing mode has not yet received a strong recommendation for implementation. Finally, there is a report on LBBP, focusing mainly on its points of differentiation from HBP.

The sympathetic nervous system in heart failure revisited.

Several attempts have been made, by the scientific community, to develop a unifying hypothesis that explains the clinical syndrome of heart failure (HF). The currently widely accepted neurohormonal model has substituted the cardiorenal and the cardiocirculatory models, which focused on salt-water retention and low cardiac output/peripheral vasoconstriction, respectively. According to the neurohormonal model, HF with eccentric left ventricular (LV) hypertrophy (LVH) (systolic HF or HF with reduced LV ejection fraction [LVEF] or HFrEF) develops and progresses because endogenous neurohormonal systems, predominantly the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS), exhibit prolonged activation following the initial heart injury exerting deleterious hemodynamic and direct nonhemodynamic cardiovascular effects. However, there is evidence to suggest that SNS overactivity often preexists HF development due to its association with HF risk factors, is also present in HF with preserved LVEF (diastolic HF or HFpEF), and that it is linked to immune/inflammatory factors. Furthermore, SNS activity in HF may be augmented by coexisting noncardiac morbidities and modified by genetic factors and demographics. The purpose of this paper is to provide a contemporary overview of the complex associations between SNS overactivity and the development and progression of HF, summarize the underlying mechanisms, and discuss the clinical implications as they relate to therapeutic interventions mitigating SNS overactivity.

Autonomic Nervous System Dysfunction in Peritoneal Dialysis Patients: An Underrecognized Cardiovascular Risk Factor?

BACKGROUND: In patients with end-stage kidney disease (ESKD) receiving peritoneal dialysis (PD), cardiovascular events represent the predominant cause of morbidity and mortality, with cardiac arrhythmias and sudden death being the leading causes of death in this population. Autonomic nervous system (ANS) dysfunction is listed among the non-traditional risk factors accounting for the observed high cardiovascular burden, with a plethora of complex and not yet fully understood pathophysiologic mechanisms being involved. SUMMARY: In recent years, preliminary studies have investigated and confirmed the presence of ANS dysfunction in PD patients, while relevant results from cohort studies have linked ANS dysfunction with adverse clinical outcomes in these patients. In light of these findings, ANS dysfunction has been recently receiving wider consideration as an independent cardiovascular risk factor in PD patients. The aim of this review was to describe the mechanisms involved in the pathogenesis of ANS dysfunction in ESKD and particularly PD patients and to summarize the existing studies evaluating ANS dysfunction in PD patients. KEY MESSAGES: ANS dysfunction in PD patients is related to multiple complex mechanisms that impair the balance between SNS/PNS, and this disruption represents a crucial intermediator of cardiovascular morbidity and mortality in this population.

Floppy Mitral Valve/Mitral Valve Prolapse and Manifestations Not Related to Mitral Regurgitation: Time to Search the Dark Side of the Moon.

BACKGROUND: Floppy mitral valve/mitral valve prolapse (FMV/MVP) is a complex entity in which several clinical manifestations are not directly related to the severity of mitral regurgitation (MR). SUMMARY: Patients with FMV/MVP and trivial to mild MR may have exercise intolerance, orthostatic phenomena, syncope/presyncope, chest pain, and ventricular arrhythmias, among others. Several anatomical and pathophysiologic consequences related to the abnormal mitral valve apparatus and to prolapse of the mitral leaflets into the left atrium provide some explanation for these symptoms. Further, it should be emphasized that MVP is a non-specific finding, while FMV (redundant mitral leaflets, elongated/rupture chordae tendineae, annular dilatation) is the central issue in the MVP story. KEY MESSAGE: The purpose of this review was to highlight the clinical manifestations of FMV/MVP not directly related to the severity of MR and to discuss the pathophysiologic mechanisms contributing to these manifestations.

Acute mitral regurgitation with and without acute heart failure.

Acute severe mitral regurgitation (MR) is rare, but often leads to cardiogenic shock, pulmonary edema, or both. Most common causes of acute severe MR are chordae tendineae (CT) rupture, papillary muscle (PM) rupture, and infective endocarditis (IE). Mild to moderate MR is often seen in patients with acute myocardial infarction (AMI). CT rupture in patients with floppy mitral valve/mitral valve prolapse is the most common etiology of acute severe MR today. In IE, native or prosthetic valve damage can occur (leaflet perforation, ring detachment, other), as well as CT or PM rupture. Since the introduction of percutaneous revascularization in AMI, the incidence of PM rupture has substantially declined. In acute severe MR, the hemodynamic effects of the large regurgitant volume into the left atrium (LA) during left ventricular (LV) systole, and in turn back into the LV during diastole, are profound as the LV and LA have not had time to adapt to this additional volume. A rapid, but comprehensive evaluation of the patient with acute severe MR is essential in order to define the underline cause and apply appropriate management. Echocardiography with Doppler provides vital information related to the underlying pathology. Coronary arteriography should be performed in patients with an AMI to define coronary anatomy and need for revascularization. In acute severe MR, medical therapy should be used to stabilize the patient before intervention (surgery, transcatheter); mechanical support is often required. Diagnostic and therapeutic steps should be individualized, and a multi-disciplinary team approach should be utilized.

Association of hydroxytyrosol enriched olive oil with vascular function in chronic coronary disease.

BACKGROUND: Hydroxytyrosol reduces low-density lipoprotein oxidation, contributing to prevention of atherosclerosis progression. METHODS: In a prospective, crossover, double-blind, placebo-controlled trial, 30 chronic coronary artery syndrome (CCAS) patients were randomized to 4 capsules/day, containing 412.5 mg olive oil with 2.5 mg hydroxytyrosol (OOHT) each one or placebo for 1 month and then were crossed over to the alternate treatment (placebo or OOHT). We measured (a) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced glycocalyx thickness), (b) flow-mediated dilation (FMD), (c) Coronary Flow Reserve (CFR) and markers of LV diastolic function by Doppler echocardiography, (d) pulse wave velocity (PWV), and (e) oxidative stress, inflammatory biomarkers and blood lipids at baseline and after treatment. RESULTS: Treatment with OOHT improved PBR, FMD, CFR and PWV compared to baseline (1.8 ± .3 vs. 1.7 ± .4 µm, p = .040, 3.7 ± 2.1 vs. 6.5% ± 2.3%, p < .001, 2.3 ± .4 vs. 2.5 ± .4, p = .030 and 11.1 ± 1.8 vs. 11.8 ± 2.3 m/s, p = .002) while there was no effect after placebo (p = NS). No effect of OOHT treatment was observed on blood pressure. There was a parallel improvement of E' of the mitral annulus and deceleration time of the E wave of mitral inflow after OOHT (p < .05) but not after placebo. Compared to baseline, treatment with OOHT reduced malondialdehyde, a marker of lipid peroxidation, oxidized LDL, triglycerides, PCSK9 and CRP blood levels (p < .05) in contrast to placebo. CONCLUSIONS: Hydroxytyrosol-enriched olive oil may have beneficial effects on endothelial, arterial and LV diastolic function likely by reducing oxidative and inflammatory burden in CCAS, though further studies are needed to confirm this mechanism.

Synergistic Pulmonoprotective Effect of Natural Prolyl Oligopeptidase Inhibitors in In Vitro and In Vivo Models of Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a highly morbid inflammatory lung disease with limited pharmacological interventions. The present study aims to evaluate and compare the potential pulmonoprotective effects of natural prolyl oligopeptidase (POP) inhibitors namely rosmarinic acid (RA), chicoric acid (CA), epigallocatechin-3-gallate (EGCG) and gallic acid (GA), against lipopolysaccharide (LPS)-induced ARDS. Cell viability and expression of pro-inflammatory mediators were measured in RAW264.7 cells and in primary murine lung epithelial and bone marrow cells. Nitric oxide (NO) production was also assessed in unstimulated and LPS-stimulated RAW264.7 cells. For subsequent in vivo experiments, the two natural products (NPs) with the most favorable effects, RA and GA, were selected. Protein, cell content and lipid peroxidation levels in bronchoalveolar lavage fluid (BALF), as well as histopathological changes and respiratory parameters were evaluated in LPS-challenged mice. Expression of key mediators involved in ARDS pathophysiology was detected by Western blotting. RA and GA favorably reduced gene expression of pro-inflammatory mediators in vitro, while GA decreased NO production in macrophages. In LPS-challenged mice, RA and GA co-administration improved respiratory parameters, reduced cell and protein content and malondialdehyde (MDA) levels in BALF, decreased vascular cell adhesion molecule-1 (VCAM-1) and the inducible nitric oxide synthase (iNOS) protein expression, activated anti-apoptotic mechanisms and down-regulated POP in the lung. Conclusively, these synergistic pulmonoprotective effects of RA and GA co-administration could render them a promising prophylactic/therapeutic pharmacological intervention against ARDS.

Long-Term Prognostic Value of Automated Measurements in Nuclear Cardiology: Comparisons with Expert Scoring.

Background and Objectives: Automated methods for the analysis of myocardial perfusion studies have been incorporated into clinical practice, but they are currently used as adjuncts to the visual interpretation. We aimed to investigate the role of automated measurements of summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) as long-term prognostic markers of morbidity and mortality, in comparison to the prognostic value of expert reading. Materials and Methods: The study was conducted at the Nuclear Medicine Laboratory of the University of Thessaly, in Larissa, Greece. A total of 378 consecutive patients with known or suspected coronary artery disease were enrolled in the study. All participants were referred to our laboratory for the performance of stress/rest myocardial perfusion single photon emission computed tomography. Automated measurements of SSS, SRS, and SDS were obtained by Emory Cardiac Toolbox (ECTb (Version 3.0), Emory University, Atlanta, GA, USA), Myovation (MYO, Xeleris version 3.05, GE Healthcare, Chicago, IL, USA), and Quantitative Perfusion SPECT (QPS (Version 4.0), Cedars-Sinai Medical Center, Los Angeles, CA, USA) software packages. Follow-up data were recorded after phone contacts, as well as through review of hospital records. Results: Expert scoring of SSS and SDS had significantly greater prognostic ability in comparison to all software packages (p < 0.001 for all comparisons). Similarly, ECTb-obtained SRS measurements had significantly lower prognostic ability in comparison to expert scoring (p < 0.001), while expert scoring of SRS showed significantly higher prognostic ability compared to MYO (p = 0.018) and QPS (p < 0.001). Conclusions: Despite the useful contribution of automated analyses in the interpretation of myocardial perfusion studies, expert reading should continue to have a crucial role, not only in clinical decision making, but also in the assessment of prognosis.

Reduction of Adverse Events With Phosphodiesterase 5 Inhibitors Post LVAD Implantation: Is It Time for a Randomized Trial?

The improved survival of patients with advanced heart failure after left ventricular assist device (LVAD) implantation together with the scarcity of donor hearts has significantly increased the population of LVAD-supported patients. However, despite the improvement in LVAD technology and the advent of third-generation continuous flow LVADs, complications such as those related to hemocompatibility and stroke rates remain ongoing clinical challenges. Thus, improvement in LVAD technology should be coupled with innovative medical management to further reduce adverse events. We have previously shown a strong association between post LVAD implant phosphodiesterase-5 inhibitors (PDE-5i) use and fewer thrombotic events, as well as improved survival in 2 observational studies. We caution, nevertheless, the use of PDE-5i based on these observations and encourage clinicians to support enrollment in a randomized control trial. A randomized control trial will determine the efficacy and safety of PDE-5i use after implantation in patients with a centrifugal flow LVAD.

Therapeutic augmentation of NO-sGC-cGMP signalling: lessons learned from pulmonary arterial hypertension and heart failure.

The nitric oxide (NO)-guanylate cyclase (GC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal function. Phosphodiesterase-5 inhibitors (PDE-5i) inhibit cGMP degradation, whereas both soluble guanylate cyclase (sGC) stimulators and sGC activators directly increase sGC. PDE-5i (e.g. sildenafil, tadalafil) and sGC stimulators (e.g. riociguat, vericiguat) have been extensively used in pulmonary artery hypertension (PAH) and heart failure (HF). PDE-5i have also been used in end-stage HF before and after left ventricular (LV) assist device (LVAD) implantation. Augmentation of NO-GC-cGMP signalling with PDE-5i causes selective pulmonary vasodilation, which is highly effective in PAH but may have controversial, potentially adverse effects in HF, including pre-LVAD implant due to device unmasking of PDE-5i-induced RV dysfunction. In contrast, retrospective analyses have demonstrated that PDE-5i have beneficial effects when initiated post LVAD implant due to the improved haemodynamics of the supported LV and the pleiotropic actions of these compounds. sGC stimulators, in turn, are effective both in PAH and in HF due to their balanced pulmonary and systemic vasodilation, and as such they are preferable to PDE-5i if the use of a pulmonary vasodilator is needed in HF patients, including those listed for LVAD implantation. Regarding the effectiveness of PDE-5i and sGC stimulators when initiated post LVAD implant, these two groups of compounds should be tested in a randomized control trial.

Pathogenesis of chronic heart failure: cardiovascular aging, risk factors, comorbidities, and disease modifiers.

Chronic heart failure (HF) is rare in the young and common in the elderly in the Western world. HF in the young is usually due to specific causes, predominantly or exclusively affecting the heart (adult congenital heart disease, different types of cardiomyopathies, myocarditis, or cardiotoxicity). In contrast, the mechanisms underlying HF development in the elderly have not been completely delineated. We propose that in most elderly patients, HF, regardless of the left ventricular ejection fraction (LVEF), is the consequence of the acceleration of cardiovascular aging by specific risk factors (usually hypertension, obesity, type 2 diabetes mellitus [T2DM], coronary artery disease [CAD], and valvular heart disease [VHD]), most affecting both the heart and the vasculature. These risk factors act individually or more commonly in groups, directly or indirectly (hypertension, obesity, and T2DM may lead to HF through an intervening myocardial infarction). The eventual HF phenotype and outcomes in the elderly are additionally dependent on the presence and/or development of comorbidities (atrial fibrillation, anemia, depression, kidney disease, pulmonary disease, sleep disordered breathing, other) and disease modifiers (race, sex, genes, other). The clinical implications of this paradigm are that aggressive treatment of hypertension, obesity, T2DM (preferably with metformin and sodium-glucose cotransporter-2 inhibitors), CAD, and VHD on top of measures that retard cardiovascular aging are the steadfast underpinning for HF prevention in the elderly, which represent the vast majority of HF patients.

Obesity, inflammation, and heart failure: links and misconceptions.

Obesity has been linked with heart failure (HF) with preserved left ventricular (LV) ejection fraction (HFpEF). This link has been attributed to obesity-induced metabolic and inflammatory disturbances leading to HFpEF. However, HF is a syndrome in which disease evolvement is associated with a dynamic unraveling of functional and structural changes leading to unique disease trajectories, creating a spectrum of phenotypes with overlapping distinct characteristics extending beyond the LV ejection fraction (LVEF). In this regard, despite quantitative differences between the two extremes (HFpEF and HF with reduced LVEF, HFrEF), there is important overlap between the phenotypes along the entire spectrum. In this paper, we describe the systemic pro-inflammatory state that is present throughout the HF spectrum and emphasize that obesity intertwines with HF beyond the LVEF construct.

Left ventricular hypertrophy and sudden cardiac death.

Sudden cardiac death (SCD) is among the leading causes of death worldwide, and it remains a public health problem, as it involves young subjects. Current guideline-directed risk stratification for primary prevention is largely based on left ventricular (LV) ejection fraction (LVEF), and preventive strategies such as implantation of a cardiac defibrillator (ICD) are justified only for documented low LVEF (i.e., ≤ 35%). Unfortunately, only a small percentage of primary prevention ICDs, implanted on the basis of a low LVEF, will deliver life-saving therapies on an annual basis. On the other hand, the vast majority of patients that experience SCD have LVEF > 35%, which is clamoring for better understanding of the underlying mechanisms. It is mandatory that additional variables be considered, both independently and in combination with the EF, to improve SCD risk prediction. LV hypertrophy (LVH) is a strong independent risk factor for SCD regardless of the etiology and the severity of symptoms. Concentric and eccentric LV hypertrophy, and even earlier concentric remodeling without hypertrophy, are all associated with increased risk of SCD. In this paper, we summarize the physiology and physiopathology of LVH, review the epidemiological evidence supporting the association between LVH and SCD, briefly discuss the mechanisms linking LVH with SCD, and emphasize the need to evaluate LV geometry as a potential risk stratification tool regardless of the LVEF.

Cardiovascular Disease, Cancer, and Multimorbidity Interactions: Clinical Implications.

BACKGROUND: With the aging population, the frequency of cardiovascular disease (CVD), cancer, and other morbid conditions is increasing dramatically. In addition, one disease may affect the other leading to a vicious cycle. SUMMARY: With aging, the function of organs and systems of the human body declines including the immune system resulting in a diminished response to various pathogens and a chronic inflammatory process; these changes, in addition to other risk factors, contribute to the development of multiple morbid conditions including CVD and cancer. Multimorbidity in the elderly has become the rule rather than the exception today. Further, this association between CVD and cancer, at least partially, is explained by both diseases sharing common risk factors and from accelerated vascular aging due to cancer and its associated therapies. Multiple studies have shown that the incidence of cancer is much higher in patients with CVD compared to the general population. These associations among CVD, cancer, and their connection to systems of the human body provide an opportunity for novel therapies. Development of new drugs should be addressed to focus on multiple systems and not just only to one disease. Further, collecting information from registries and processing large amounts of data using artificial intelligence may assist the clinician when treating an individual patient in the future. KEY MESSAGES: As the aging population increases, CVD, cancer, and multimorbidity will continue to constitute a major health problem in the years to come. The physician who is taking care of such a patient, in addition to knowledge, requires clinical wisdom, clinical experience, and common sense in order to apply the continuous evolving knowledge to the individual patient.

Myocardial Protection and Current Cancer Therapy: Two Opposite Targets with Inevitable Cost.

Myocardial protection against ischemia/reperfusion injury (IRI) is mediated by various ligands, activating different cellular signaling cascades. These include classical cytosolic mediators such as cyclic-GMP (c-GMP), various kinases such as Phosphatydilinositol-3- (PI3K), Protein Kinase B (Akt), Mitogen-Activated-Protein- (MAPK) and AMP-activated (AMPK) kinases, transcription factors such as signal transducer and activator of transcription 3 (STAT3) and bioactive molecules such as vascular endothelial growth factor (VEGF). Most of the aforementioned signaling molecules constitute targets of anticancer therapy; as they are also involved in carcinogenesis, most of the current anti-neoplastic drugs lead to concomitant weakening or even complete abrogation of myocardial cell tolerance to ischemic or oxidative stress. Furthermore, many anti-neoplastic drugs may directly induce cardiotoxicity via their pharmacological effects, or indirectly via their cardiovascular side effects. The combination of direct drug cardiotoxicity, indirect cardiovascular side effects and neutralization of the cardioprotective defense mechanisms of the heart by prolonged cancer treatment may induce long-term ventricular dysfunction, or even clinically manifested heart failure. We present a narrative review of three therapeutic interventions, namely VEGF, proteasome and Immune Checkpoint inhibitors, having opposing effects on the same intracellular signal cascades thereby affecting the heart. Moreover, we herein comment on the current guidelines for managing cardiotoxicity in the clinical setting and on the role of cardiovascular confounders in cardiotoxicity.

Automated Analysis vs. Expert Reading in Nuclear Cardiology: Correlations with the Angiographic Score.

Background and Objectives: Myocardial perfusion imaging (MPI) has an important role in the non-invasive investigation of coronary artery disease. The interpretation of MPI studies is mainly based on the visual evaluation of the reconstructed images, while automated quantitation methods may add useful data for each patient. However, little evidence is currently available regarding the actual incremental clinical diagnostic performance of automated MPI analysis. In the present study, we aimed to assess the correlation between automated measurements of Summed Stress Score (SSS), Summed Rest Score (SRS) and Summed Difference Score (SDS), with the corresponding expert reading values, using coronary angiography as the gold standard. Materials and Methods: The study was conducted at the Nuclear Medicine Laboratory of the University Hospital of Larissa, Larissa, Greece, οver an one-year period (January 2019-January 2020). 306 patients, with known or suspected coronary artery disease, were enrolled in the study. Each participant underwent a coronary angiography, prior to or after the scintigraphic study (within a three-month period). Either symptom-limited treadmill test, or pharmacologic testing using adenosine or regadenoson, was performed in all participants, and the scintigraphic studies were carried out using technetium 99m (99mTc) tetrofosmin (one-day stress/rest protocol). Coronary angiographies were scored according to a 4-point scoring system (angiographic score; O: normal study, 1: one-vessel disease, 2: two-vessel disease, 3: three-vessel disease). Moreover, automated measurements of SSS, SRS and SDS were derived by three widely available software packages (Emory Cardiac Toolbox, Myovation, Quantitative Perfusion SPECT). Results: Interclass Correlation Coefficients of SSS, SRS and SDS between expert reading and software packages were moderate to excellent. Visually defined SSS, SRS and SDS were significantly correlated with the corresponding results of all software packages. However, visually defined SSS, SRS and SDS were more strongly correlated with the angiographic score, indicating a better performance of expert reading when compared to automated analysis. Conclusions: Based on our results, visual evaluation continues to have a crucial role for the interpretation of MPI images. Software packages can provide automated measurements of several parameters, particularly contributing to the investigation of cases with ambiguous scintigraphic findings.

Renin-angiotensin-system inhibition in the context of corona virus disease-19: experimental evidence, observational studies, and clinical implications.

Coronavirus disease 2019 (COVID-19) is due to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 which binds and enters the host cells through the angiotensin-converting enzyme (ACE)2. While the potential for benefit with the use of renin-angiotensin-aldosterone system inhibitors (RAASi) and the risks from stopping them is more evident, potential harm by RAΑSi may also be caused by the increase in the activity of the ACE2 receptor, the inefficient counter regulatory axis in the lungs in which the proinflammatory prolyloligopeptidase (POP) is the main enzyme responsible for the conversion of deleterious angiotensin (ANG) II to protective ANG [1-7] and the proinflammatory properties of ACE2(+) cells infected with SARS-CoV-2. Acknowledging the proven RAΑSi benefit in patients with several diseases such as hypertension, heart failure, coronary disease, and diabetic kidney disease in the non-COVID-19 era, it is a reasonable strategy in this period of uncertainty to use these agents judiciously with careful consideration and to avoid the use of RAASi in select patients whenever possible, until definitive evidence becomes available.

The Counter Regulatory Axis of the Lung Renin-Angiotensin System in Severe COVID-19: Pathophysiology and Clinical Implications.

The severe acute respiratory syndrome coronavirus (SARS-CoV)-2, which is responsible for coronavirus disease 2019 (COVID-19), uses angiotensin (ANG)-converting enzyme 2 (ACE2) as the entrance receptor. Although most COVID-19 cases are mild, some are severe or critical, predominantly due to acute lung injury. It has been widely accepted that a counter regulatory renin-angiotensin system (RAS) axis including the ACE2/ANG [1-7]/Mas protects the lungs from acute lung injury. However, recent evidence suggests that the generation of protective ANG [1-7] in the lungs is predominantly mediated by proinflammatory prolyl oligopeptidase (POP), which has been repeatedly demonstrated to be involved in lung pathology. This review contends that acute lung injury in severe COVID-19 is characterised by a) ACE2 downregulation and malfunction (inflammatory signalling) due to viral occupation, and b) dysregulation of the protective RAS axis, predominantly due to increased activity of proinflammatory POP. It follows that a reasonable treatment strategy in COVID-19-related acute lung injury would be delivering functional recombinant (r) ACE2 forms to trap the virus. Additionally, or alternatively to rACE2 delivery, the potential benefits resulting from lowering POP activity should also be explored. These treatment strategies deserve further investigation.

Adult congenital heart disease with pulmonary arterial hypertension: mechanisms and management.

Adult congenital heart disease (ACHD) encompasses a range of structural cardiac abnormalities present before birth attributable to abnormal foetal cardiac development. The pulmonary circulation of patients with ACHD and intracardiac or extracardiac defects is often exposed to increased blood flow and occasionally to systemic pressures. Depending on the location and magnitude of the defect as well as the time of surgical correction, the patient with ACHD is at risk of developing pulmonary arterial hypertension (PAH), which dramatically increases morbidity and mortality. It is encouraging that therapies applied in idiopathic PAH and significantly improve outcome are also effective in ACHD-related PAH (ACHD-PAH). This review summarizes the challenges encountered in the diagnosis and management of ACHD-PAH.