In-hospital versus after-discharge complete revascularization in patients with ST segment elevation myocardial infarction and multivessel disease. REVIVA-ST trial.

INTRODUCTION: Complete revascularization (CR) in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD), is associated with a reduction in major adverse cardiovascular events (MACE). However, there is uncertainty about whether nonculprit-lesion revascularization should be performed, during index hospitalization or delayed, especially regarding health care resources utilization. In this study, we aimed to evaluate the impact of in-hospital nonculprit-lesion revascularization vs. delayed (after discharge) revascularization on the length of index hospitalization. METHODS: In this single-center study, we randomly assigned patients with STEMI and MVD who underwent successful culprit-lesion PCI to a strategy of either CR during in-hospital admission or a delayed CR after discharge. The first primary endpoint was the length of hospital stay. The second endpoint was the composite of cardiovascular death, myocardial infarction or ischemia-driven revascularization at 12 months (MACE). RESULTS: From January 2018 to December 2022, we enrolled 258 patients (131 allocated to CR during in-hospital admission and 127 to an after-discharge CR). We found a significant reduction in the length of hospital stay in those assigned to after-discharge CR strategy [4 days (3-5) versus 7 days (5-9); p = 0.001]. At 12-month of follow-up, no differences were found in the occurrence of MACE, 7 (5.34%) patients in in-hospital CR and 4 (3.15%) in after-discharge CR strategy; (hazard ratio, 0.59; 95% confidence interval, 0.17 to 2.02; p = 0.397). CONCLUSIONS: In STEMI patients with MVD, an after-discharge CR strategy reduces the length of index hospitalization without an increased risk of MACE after 12 months of follow-up. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT04743154.

Chronic airway epithelial hypoxia exacerbates injury in muco-obstructive lung disease through mucus hyperconcentration.

Unlike solid organs, human airway epithelia derive their oxygen from inspired air rather than the vasculature. Many pulmonary diseases are associated with intraluminal airway obstruction caused by aspirated foreign bodies, virus infection, tumors, or mucus plugs intrinsic to airway disease, including cystic fibrosis (CF). Consistent with requirements for luminal O2, airway epithelia surrounding mucus plugs in chronic obstructive pulmonary disease (COPD) lungs are hypoxic. Despite these observations, the effects of chronic hypoxia (CH) on airway epithelial host defense functions relevant to pulmonary disease have not been investigated. Molecular characterization of resected human lungs from individuals with a spectrum of muco-obstructive lung diseases (MOLDs) or COVID-19 identified molecular features of chronic hypoxia, including increased EGLN3 expression, in epithelia lining mucus-obstructed airways. In vitro experiments using cultured chronically hypoxic airway epithelia revealed conversion to a glycolytic metabolic state with maintenance of cellular architecture. Chronically hypoxic airway epithelia unexpectedly exhibited increased MUC5B mucin production and increased transepithelial Na+ and fluid absorption mediated by HIF1α/HIF2α-dependent up-regulation of ß and γENaC (epithelial Na+ channel) subunit expression. The combination of increased Na+ absorption and MUC5B production generated hyperconcentrated mucus predicted to perpetuate obstruction. Single-cell and bulk RNA sequencing analyses of chronically hypoxic cultured airway epithelia revealed transcriptional changes involved in airway wall remodeling, destruction, and angiogenesis. These results were confirmed by RNA-in situ hybridization studies of lungs from individuals with MOLD. Our data suggest that chronic airway epithelial hypoxia may be central to the pathogenesis of persistent mucus accumulation in MOLDs and associated airway wall damage.

Long-term recurrent events in ST-elevation myocardial infarction and multivessel disease. The impact of different revascularization strategies.

INTRODUCTION: The benefit of complete revascularization (CR) on long-term total event reduction in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD), still remains unclear. We assessed the efficacy of three different revascularization strategies on long-term total recurrent events. METHODS: We retrospectively analyzed 414 consecutive patients admitted with STEMI and MVD who were categorized according to the revascularization strategy used: culprit-vessel-only percutaneous coronary intervention (PCI) (n=163); in-hospital CR (n=136); and delayed CR (n=115). The combined endpoint assessed was all-cause mortality, the total number of myocardial infarctions, ischemia-driven revascularizations or strokes. Negative binomial regression was used to assess the association between the revascularization strategy and total events; risk estimates were expressed as an incidence rates ratio (IRR). RESULTS: At a median follow-up of four years (1.2-6), rates of the combined endpoint per 10 patient-years were 18, 0.8, and 0.6 in culprit-vessel-only PCI, in-hospital CR, and delayed CR strategies, respectively (p<0.001). After multivariable adjustment and when compared with culprit-vessel-only PCI, both in-hospital and delayed CR strategies were significantly associated with a reduction in the combined endpoint (IRR=0.40: 95% confidence interval (CI), 0.25-0.64; p<0.001; and IRR 0.40: 95% CI, 0.24-0.62; p<0.001, respectively). No differences were observed across in-hospital and delayed CR strategies. CONCLUSIONS: Complete revascularization of non-culprit lesions in patients with STEMI and MVD reduces the risk of total recurrent events during long-term follow-up. No differences between in-hospital and delayed CR strategies were found.

Inaccuracy of a non-invasive estimation of pulmonary vascular resistance assessed by cardiovascular magnetic resonance in heart failure patients.

Pulmonary vascular resistance (PVR) is a marker of pulmonary vascular remodeling. A non-invasive model assessed by cardiovascular magnetic resonance (CMR) has been proposed to estimate PVR. However, its accuracy has not yet been evaluated in patients with heart failure. We prospectively included 108 patients admitted with acute heart failure (AHF), in whom a right heart catheterization (RHC) and CMR were performed at the same day. PVR was estimated by CMR applying the model: PVR = 19.38 - [4.62 × Ln pulmonary artery average velocity (in cm/s)] - [0.08 × right ventricle ejection fraction (in %)], and by RHC using standard formulae. The median age of the cohort was 67 years (interquartile range 58-73), and 34% were females. The median of PVR assessed by RHC and CMR were 2.2 WU (1.5-4) and 5 WU (3.4-7), respectively. We found a weak correlation between invasive PVR and PVR assessed by CMR (Spearman r = 0.21, p = 0.02). The area under the ROC curve for PVR assessed by CMR to detect PVR ≥ 3 WU was 0.57, 95% confidence interval (CI): 0.47-0.68. In patients with AHF, the non-invasive estimation of PVR using CMR shows poor accuracy, as well as a limited capacity to discriminate increased PVR values.

Long-term outcomes and predictors of morbi-mortality according to age in stemi patients with multivessel disease: Impact of an incomplete revascularization.

BACKGROUND: Optimal management strategy for patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD) still remains unclear, especially in the elderly population. The aim of this study was to assess long-term outcomes and predictors of morbi-mortality according to age in patients with a STEMI and MVD. METHODS: We prospectively included 381 consecutive patients with a STEMI who underwent primary angioplasty and showed MVD in the angiogram. 111 (29.1%) patients were older than 75 (≥75) years and 270 (70.9%) were younger than 75 (<75) years. The co-primary outcomes were the incidence of all-cause mortality and major adverse cardiac events (MACE) during follow-up. RESULTS: During a median follow-up of 22 months, patients ≥75 years showed a higher incidence of all-cause mortality and MACE, as compared to younger patients. On multivariate analysis, incomplete revascularization (IR) was only an independent predictor of MACE (HR = 3.1, CI 95%:1.9-4.7; P = .02) in younger patients; whereas in the elderly group severely depressed ejection fraction was the unique independent predictor of MACE (HR = 2.7, CI 95%:1.5-4.8; P = .001). IR was not associated with the risk of all-cause mortality in any group. CONCLUSION: This study confirms the relevant prevalence of MVD in STEMI patients, as well as the difference in outcomes of an IR strategy between both age-groups, being only independently associated with MACE in younger patients. This finding supports that a routine complete revascularization (CR) strategy seems to be the best therapeutic option in younguer patients, whereas in the elderly population may not confer a clear clinical benefit during a long-term follow-up.

Infantile Aortic Coarctation in an Adult with Heart Failure.

OBJECTIVE: The aim of this case report is to highlight the importance of excluding aortic coarctation in a patient with a bicuspid aortic valve. CLINICAL PRESENTATION AND INTERVENTION: A 56-year-old woman with hypertension was admitted complaining of progressive dyspnea. Transthoracic echocardiography showed a calcified, bicuspid aortic valve with severe stenosis. Aortography revealed the presence of severe narrowing of the aorta between the carotid and subclavian arteries. The patient was referred for cardiovascular surgery in which successful aortic valve replacement and aortic correction were performed. CONCLUSION: This case report shows an uncommon finding of infantile aortic coarctation in an adult patient admitted with heart failure.

Cardiac rupture and tamponade during ventriculography.

Left ventricular free wall rupture after a myocardial infarction is a complication which is unusually seen during ventriculography. We present the case of a patient who developed a cardiac rupture and tamponade captured on ventriculography.

Mucin granule intraluminal organization.

Mucus secretions have played a central role in the evolution of multicellular organisms, enabling adaptation to widely differing environments. In vertebrates, mucus covers and protects the epithelial cells in the respiratory, gastrointestinal, urogenital, visual, and auditory systems, amphibian's epidermis, and the gills in fishes. Deregulation of mucus production and/or composition has important consequences for human health. For example, mucus obstruction of small airways is observed in chronic airway diseases, including chronic obstructive pulmonary disease, asthma, and cystic fibrosis. The major protein component in the mucus is a family of large, disulfide-bonded glycoproteins known as gel-forming mucins. These proteins are accumulated in large, regulated secretory granules (the mucin granules) that occupy most of the apical cytoplasm of specialized cells known as mucous/goblet cells. Since mucin oligomers have contour dimensions larger than the mucin granule average diameter, the question arises how these highly hydrophilic macromolecules are organized within these organelles. I review here the intraluminal organization of the mucin granule in view of our knowledge on the structure, biosynthesis, and biophysical properties of gel-forming mucins, and novel imaging studies in living mucous/goblet cells. The emerging concept is that the mucin granule lumen comprises a partially condensed matrix meshwork embedded in a fluid phase where proteins slowly diffuse.

Mucin granule intraluminal organization in living mucous/goblet cells. Roles of protein post-translational modifications and secretion.

Recent studies suggest that the mucin granule lumen consists of a matrix meshwork embedded in a fluid phase. Secretory products can both diffuse, although very slowly, through the meshwork pores and interact noncovalently with the matrix. Using a green fluorescent protein-mucin fusion protein (SHGFP-MUC5AC/CK) as a FRAP (fluorescence recovery after photobleaching) probe, we have assessed in living mucous cells the relative importance of different protein post-translational modifications on the intragranular organization. Long term inhibition of mucin-type O-glycosylation, sialylation, or sulfation altered SHGFP-MUC5AC/CK characteristic diffusion time (t(1/2)), whereas all but sulfation diminished its mobile fraction. Reduction of protein disulfide bonds with tris(hydroxypropyl)phosphine resulted in virtually complete immobilization of the SHGFP-MUC5AC/CK intragranular pool. However, when activity of the vacuolar H+-ATPase was also inhibited, disulfide reduction decreased SHGFP-MUC5AC/CK t((1/2)) while diminishing its intraluminal concentration. Similar FRAP profiles were observed in granules that remained in the cells after the addition of a mucin secretagogue. Taken together these results suggest that: (a) the relative content of O-glycans and intragranular anionic groups is crucial for protein diffusion through the intragranular meshwork; (b) protein-protein, rather than carbohydrate-mediated, interactions are responsible for binding of SHGFP-MUC5AC/CK to the immobile fraction, although the degree of matrix O-glycosylation and sialylation affects such interactions; (c) intragranular organization does not depend on covalent multimerization of mucins or the presence of native disulfide bonds in the intragranular mucin/proteins, but rather on specific protein-mediated interactions that are important during the early stages of mucin matrix condensation; (d) alterations of the intragranular matrix precede granule discharge, which can be partial and, accordingly, does not necessarily involve the disappearance of the granule.

[Non-invasive assessment of coronary artery bypass grafts by computed tomography: comparison with conventional coronary angiography]. / Valoración no invasiva de injertos coronarios con tomografía computarizada: comparación con la angiografía convencional.

INTRODUCTION AND OBJECTIVES: Although it has been demonstrated that the diagnostic accuracy of computed tomography in the non-invasive assessment of major epicardial coronary arteries is high, only a few studies have evaluated the technique's reliability in assessing coronary artery bypass grafts. The aim of this study was to determine the diagnostic accuracy of multidetector computed tomography in the assessment of coronary grafts. PATIENTS AND METHOD: We prospectively evaluated 117 coronary grafts in 38 patients who had undergone coronary artery bypass graft surgery and who had a clinical indication for angiographic graft assessment. All patients were in sinus rhythm and had a heart rate below 75 bpm. A 16-detector scanner was used for non-invasive assessment of the coronary grafts at a slice thickness of 1.2 mm. The diagnostic accuracy of computed tomography in the non-invasive assessment of significant lesions (i.e., occluded lesions or those with a stenosis greater than 50%) in coronary artery bypass grafts was evaluated by comparison with the results of conventional angiography. RESULTS: Of the 117 grafts evaluated, 99 (84.6%) were visualized by conventional angiography and 109 (93.2%) by computed tomography. Overall, 98 grafts were analyzed using both techniques. The sensitivity and specificity of computed tomography in detecting significant lesions were: 92% and 97.3%, respectively, for all grafts; 89.5% and 97.6%, respectively, for venous grafts; and 100% and 96.8%, respectively, for arterial grafts. CONCLUSIONS: The diagnostic accuracy of multidetector computed tomography in coronary artery bypass graft assessment was high.

Valoración no invasiva de injertos coronarios con tomografía computarizada: comparación con la angiografía convencional / Non-invasive assessment of coronary artery bypass grafts by computed tomography: comparison with conventional coronary angiography

Introducción y objetivos. Aunque la tomografía computarizada (TC) muestra una elevada exactitud diagnóstica en la valoración no invasiva de las arterias coronarias principales, son todavía escasos los trabajos que valoren su fiabilidad en el estudio de los injertos coronarios. El objetivo de este estudio es determinar la exactitud diagnóstica de la TC con detectores múltiples en la valoración de los injertos coronarios. Pacientes y método. Se evaluó de manera prospectiva a 38 pacientes revascularizados quirúrgicamente (117 injertos coronarios según la hoja operatoria), con indicación clínica de evaluación angiográfica de sus injertos. Todos los pacientes se encontraban en ritmo sinusal y con una frecuencia cardíaca 50% u oclusión) y los resultados se compararon con los de la angiografía convencional. Resultados. De los 117 injertos referidos se visualizaron 99 (84,6%) mediante angiografía convencional y 109 (93,2%) mediante TC. Se analizaron los 98 injertos valorados por ambas técnicas. Los valores de sensibilidad y especificidad de la TC para el total de injertos fueron del 92 y del 97,3%, para los injertos venosos del 89,5 y del 97,6%, y para los injertos arteriales del 100 y del 96,8%, respectivamente. Conclusiones. La TC con detectores múltiples muestra una elevada exactitud diagnóstica en la valoración de los injertos coronarios

Introduction and objectives. Although it has been demonstrated that the diagnostic accuracy of computed tomography in the non-invasive assessment of major epicardial coronary arteries is high, only a few studies have evaluated the technique's reliability in assessing coronary artery bypass grafts. The aim of this study was to determine the diagnostic accuracy of multidetector computed tomography in the assessment of coronary grafts. Patients and method. We prospectively evaluated 117 coronary grafts in 38 patients who had undergone coronary artery bypass graft surgery and who had a clinical indication for angiographic graft assessment. All patients were in sinus rhythm and had a heart rate below 75 bpm. A 16-detector scanner was used for non-invasive assessment of the coronary grafts at a slice thickness of 1.2 mm. The diagnostic accuracy of computed tomography in the non-invasive assessment of significant lesions (i.e., occluded lesions or those with a stenosis greater than 50%) in coronary artery bypass grafts was evaluated by comparison with the results of conventional angiography. Results. Of the 117 grafts evaluated, 99 (84.6%) were visualized by conventional angiography and 109 (93.2%) by computed tomography. Overall, 98 grafts were analyzed using both techniques. The sensitivity and specificity of computed tomography in detecting significant lesions were: 92% and 97.3%, respectively, for all grafts; 89.5% and 97.6%, respectively, for venous grafts; and 100% and 96.8%, respectively, for arterial grafts. Conclusions. The diagnostic accuracy of multidetector computed tomography in coronary artery bypass graft assessment was high

Mucin granules are in close contact with tubular elements of the endoplasmic reticulum.

Live cell imaging methods were used to characterize goblet cells expressing a MUC5AC domain fused to enhanced green fluorescent protein that labels the granule lumen. Golgi complex and endosome/lysosome elements largely resided in the periphery of the granular mass. On the contrary, a tubular meshwork of endoplasmic reticulum (ER) was in close contact with the mucin granules. This meshwork could be identified in fixed native human bronchial goblet cells labeled with an anti-calreticulin antibody. The potential biological significance of this ER network for mucin secretion is discussed.

Chronic airway infection/inflammation induces a Ca2+i-dependent hyperinflammatory response in human cystic fibrosis airway epithelia.

Hyperinflammatory responses to infection have been postulated as a component of cystic fibrosis (CF) lung disease. Studies have linked intracellular calcium (Ca(2+)(i)) mobilization with inflammatory responses in several systems. We have reported that the pro-inflammatory mediator bradykinin (BK) promotes larger Ca(2+)(i) signals in CF compared with normal bronchial epithelia, a response that reflects endoplasmic reticulum (ER)/Ca(2+) store expansion induced by chronic luminal airway infection/inflammation. The present study investigated whether CF airway epithelia were hyperinflammatory and, if so, whether the hyperinflammatory CF phenotype was linked to larger Ca(2+) stores in the ER. We found that DeltaF508 CF bronchial epithelia were hyperinflammatory as defined by an increased basal and mucosal BK-induced interleukin (IL)-8 secretion. However, the CF hyperinflammation expressed in short-term (6-11-day-old) primary cultures of DeltaF508 bronchial epithelia was lost in long-term (30-40-day-old) primary cultures of DeltaF508 bronchial epithelia, indicating this response was independent of mutant cystic fibrosis transmembrane conductance regulator. Exposure of 30-40-day-old cultures of normal airway epithelia to supernatant from mucopurulent material (SMM) from CF airways reproduced the increased basal and mucosal BK-stimulated IL-8 secretion of short-term CF cultures. The BK-triggered increased IL-8 secretion in SMM-treated cultures was mediated by an increased Ca(2+)(i) mobilization consequent to an ER expansion associated with increases in protein synthesis (total, cytokines, and antimicrobial factors). The increased ER-dependent, Ca(2+)(i)-mediated hyperinflammatory epithelial response may represent a general beneficial airway epithelial adaptation to transient luminal infection. However, in CF airways, the Ca(2+)(i)-mediated hyperinflammation may be ineffective in promoting the eradication of infection in thickened mucus and, consequently, may have adverse effects in the lung.

pH-dependent intraluminal organization of mucin granules in live human mucous/goblet cells.

To study the mechanism of gel-forming mucin packaging within mucin granules, we generated human mucous/goblet cells stably expressing a recombinant MUC5AC domain fused to green fluorescent protein (GFP). The fusion protein, named SHGFP-MUC5AC/CK, accumulated in the granules together with native MUC5AC. Inhibition of protein synthesis or disorganization of the Golgi complex did not result in diminished intragranular SHGFP-MUC5AC/CK signals, consistent with long-term storage of the fusion protein. However, SHGFP-MUC5AC/CK was rapidly discharged from the granules upon incubation of the cells with ATP, an established mucin secretagogue. Several criteria indicated that SHGFP-MUC5AC/CK was not covalently linked to endogenous MUC5AC. Analysis of fluorescence recovery after photobleaching suggested that the intragranular SHGFP-MUC5AC/CK mobile fraction and mobility were significantly lower than in the endoplasmic reticulum lumen. Incubation of the cells with bafilomycin A1, a specific inhibitor of the vacuolar H+-ATPase, did not alter the fusion protein mobility, although it significantly increased (approximately 20%) the intragranular SHGFP-MUC5AC/CK mobile fraction. In addition, the granules in bafilomycin-incubated cells typically exhibited a heterogeneous intraluminal distribution of the fluorescent fusion protein. These results are consistent with a model of mucin granule intraluminal organization with two phases: a mobile phase in which secretory proteins diffuse as in the endoplasmic reticulum lumen but at a lower rate and an immobile phase or matrix in which proteins are immobilized by noncovalent pH-dependent interactions. An intraluminal acidic pH, maintained by the vacuolar H+-ATPase, is one of the critical factors for secretory protein binding to the immobile phase and also for its organization.

Reevaluating gel-forming mucins' roles in cystic fibrosis lung disease.

The existence of mucus plugs, containing mucins, bacteria, and neutrophils, blocking the lower airways in the lung of cystic fibrosis (CF) patients has raised the possibility that production of "abnormal" mucins is a critical characteristic of this disease. The molecular nature, if any, of this abnormality is unknown. Recent studies suggest that CF lung disease progression is characterized by an early phase in which airway surface liquid (ASL) increased dehydration is accompanied by altered pH and levels of reduced glutathione (GSH). In a later phase, bacterial infection and neutrophil invasion lead to increased ASL of concentrations myeloperoxidase and hypochlorous acid (HOCl). Independent studies indicate that gel-forming mucins, the key components of airway mucus, form disulfide-linked polymers through a pH-dependent, likely self-catalyzed mechanism. In this article, we present the hypothesis that increased mucus concentration (dehydration) and altered pH, and levels of GSH, myeloperoxidase, and/or HOCl result in the extracellular formation of additional interchain bonds among airway mucins. These novel interactions would create an atypical mucin network with abnormal viscoelastic and adhesive properties.

C-Mannosylation of MUC5AC and MUC5B Cys subdomains.

We expressed recombinant Cys subdomains in COS-7 cells to examine the role of this highly conserved protein domain in mucin biosynthesis. The entire Cys1 and Cys5 and Cys1 and Cys3 subdomains in MUC5AC and MUC5B, respectively, each with six carboxyl terminal histidine residues, were pulse-labeled with [(35)S]cysteine/methionine, and the labeled proteins were examined in the culture medium. Under nonreducing conditions, secreted Cys subdomains were monomers, indicating the absence of interchain disulfide bonds. Cross-linking studies suggested the domains are able to interact through very weak noncovalent interactions. Though the domains had apparent M(r) consistent with the absence of N- and O-glycans, they could be purified with mannose-specific lectins. Lectin binding was prevented by mutation of the first tryptophan residue in the putative C-mannosylation acceptor motif WXXW, indicating that C-mannosylation is responsible for lectin binding. As judged by pulse-chase experiments, C-mannosylation occurred very early during the domain biosynthesis, likely in the endoplasmic reticulum (ER). Mutation of the WXXW motif or expression of the unmutated domain in CHO-Lec35.1 cells, a C-mannosylation-defective cell line, resulted in reduced secretion of the corresponding Cys subdomains. Live cell imaging of green fluorescent protein fused to the Cys subdomains clearly revealed increased presence of Cys subdomains in the ER of CHO-Lec35.1 cells when compared to the same domains expressed in CHO-K1 cells. Considered together, these studies suggest that the Cys subdomains of MUC5AC and MUC5B are C-mannosylated in their respective WXXW motifs. C-mannosylation is likely required for proper folding of the Cys subdomains and/or for some aspect of ER export during mucin biosynthesis.