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TGF-β is essential for vascular development; however, excess TGF-β signaling promotes thoracic aortic aneurysm and dissection in multiple disorders, including Marfan syndrome. Since the pathology of TGF-β overactivity manifests primarily within the arterial media, it is widely assumed that suppression of TGF-β signaling in vascular smooth muscle cells will ameliorate aortic disease. We tested this hypothesis by conditional inactivation of Tgfbr2, which encodes the TGF-β type II receptor, in smooth muscle cells of postweanling mice. Surprisingly, the thoracic aorta rapidly thickened, dilated, and dissected in these animals. Tgfbr2 disruption predictably decreased canonical Smad signaling, but unexpectedly increased MAPK signaling. Type II receptor-independent effects of TGF-β and pathological responses by nonrecombined smooth muscle cells were excluded by serologic neutralization. Aortic disease was caused by a perturbed contractile apparatus in medial cells and growth factor production by adventitial cells, both of which resulted in maladaptive paracrine interactions between the vessel wall compartments. Treatment with rapamycin restored a quiescent smooth muscle phenotype and prevented dissection. Tgfbr2 disruption in smooth muscle cells also accelerated aneurysm growth in a murine model of Marfan syndrome. Our data indicate that basal TGF-β signaling in smooth muscle promotes postnatal aortic wall homeostasis and impedes disease progression.

Mitral valve prolapse is often benign, but progression to mitral regurgitation may require invasive intervention and there is no specific medical therapy. An association of mitral valve prolapse with Marfan syndrome resulting from pathogenic FBN1 variants supports the use of hypomorphic fibrillin-1 mgR mice to investigate mechanisms and therapy for mitral valve disease. mgR mice developed severe myxomatous mitral valve degeneration with mitral regurgitation by 12 weeks of age. Persistent activation of TGF-β and mTOR signaling along with macrophage recruitment preceded histological changes at 4 weeks of age. Short-term mTOR inhibition with rapamycin from 4 to 5 weeks of age prevented TGF-β overactivity and leukocytic infiltrates, while long-term inhibition of mTOR or TGF-β signaling from 4 to 12 weeks of age rescued mitral valve leaflet degeneration. Transcriptomic analysis identified integrins as key receptors in signaling interactions, and serologic neutralization of integrin signaling or a chimeric integrin receptor altering signaling prevented mTOR activation. We confirmed increased mTOR signaling and a conserved transcriptome signature in human specimens of sporadic mitral valve prolapse. Thus, mTOR activation from abnormal integrin-dependent cell-matrix interactions drives TGF-β overactivity and myxomatous mitral valve degeneration, and mTOR inhibition may prevent disease progression of mitral valve prolapse.

Smooth muscle cell (SMC) proliferation has been thought to limit the progression of thoracic aortic aneurysm and dissection (TAAD) because loss of medial cells associates with advanced disease. We investigated effects of SMC proliferation in the aortic media by conditional disruption of Tsc1, which hyperactivates mTOR complex 1. Consequent SMC hyperplasia led to progressive medial degeneration and TAAD. In addition to diminished contractile and synthetic functions, fate-mapped SMCs displayed increased proteolysis, endocytosis, phagocytosis, and lysosomal clearance of extracellular matrix and apoptotic cells. SMCs acquired a limited repertoire of macrophage markers and functions via biogenesis of degradative organelles through an mTOR/β-catenin/MITF-dependent pathway, but were distinguishable from conventional macrophages by an absence of hematopoietic lineage markers and certain immune effectors even in the context of hyperlipidemia. Similar mTOR activation and induction of a degradative SMC phenotype in a model of mild TAAD due to Fbn1 mutation greatly worsened disease with near-uniform lethality. The finding of increased lysosomal markers in medial SMCs from clinical TAAD specimens with hyperplasia and matrix degradation further supports the concept that proliferation of degradative SMCs within the media causes aortic disease, thus identifying mTOR-dependent phenotypic modulation as a therapeutic target for combating TAAD.

Medial degeneration is a common histopathological finding in aortopathy and is considered a mechanism for dilatation. We investigated if medial degeneration is specific for sporadic thoracic aortic aneurysms versus nondilated aortas. Specimens were graded by pathologists, blinded to the clinical diagnosis, according to consensus histopathological criteria. The extent of medial degeneration by qualitative (semi-quantitative) assessment was not specific for aneurysmal compared to nondilated aortas. In contrast, blinded quantitative assessment of elastin amount and medial cell number distinguished aortic aneurysms and referent specimens, albeit with marked overlap in results. Specifically, the medial fraction of elastin decreased from dilution rather than loss of protein as cross-sectional amount was maintained while the cross-sectional number, though not density, of smooth muscle cells increased in proportion to expansion of the media. Furthermore, elastic lamellae did not thin and interlamellar distance did not diminish as expected for lumen dilatation, implying a net gain of lamellar elastin and intralamellar cells or extracellular matrix during aneurysmal wall remodeling. These findings support the concepts that: (1) medial degeneration need not induce aortic aneurysms, (2) adaptive responses to altered mechanical stresses increase medial tissue, and (3) greater turnover, not loss, of mural cells and extracellular matrix associates with aortic dilatation.

Patients with aortic root abscesses experience increased morbidity and mortality compared to those without abscess in aortic valve infective endocarditis. The superior intervention for patients with aortic root abscess is not determined. This research investigates the degree to which increased morbidity and mortality of aortic root abscess, and to describe perioperative characteristics and outcomes of root operations versus root-sparing repairs of aortic root abscess. All patients who underwent surgical treatment of active aortic valve endocarditis between 2011 and 2022 at a single institution were reviewed, yielding 218 patients, of whom 64 had perivalvular abscess. Patients were treated with either simple (root-sparing) or complex (root replacement) techniques. Patients with abscess demonstrated significantly higher rates of previous cardiac surgery, redo endocarditis surgery, aortocavitary fistula, heart block, and prosthetic valve endocarditis. One quarter of abscesses were not detected on preoperative imaging. Presence of abscess was a significant predictor of operative mortality. Prosthetic valve endocarditis was a significant predictor of complex repair in patients with abscess. Five-year survival was similar between simple and complex repair groups in patients with abscess. Aortic root abscess confers significant morbidity and mortality, and measures should be taken to ensure early detection and treatment of this condition.

Internalization of complement membrane attack complexes (MACs) assembles NLRP3 inflammasomes in endothelial cells (EC) and promotes IL-β-mediated tissue inflammation. Informed by proteomics analyses of FACS-sorted inflammasomes, we identify a protein complex modulating inflammasome activity on endosomes. ZFVYE21, a Rab5 effector, partners with Rubicon and RNF34, forming a “ZRR” complex that is stabilized in a Rab5- and ZFYVE21-dependent manner on early endosomes. There, Rubicon competitively disrupts inhibitory associations between caspase-1 and its pseudosubstrate, Flightless I (FliI), while RNF34 ubiquitinylates and degradatively removes FliI from the signaling endosome. The concerted actions of the ZRR complex increase pools of endosome-associated caspase-1 available for activation. The ZRR complex is assembled in human tissues, its associated signaling responses occur in three mouse models in vivo, and the ZRR complex promotes inflammation in a skin model of chronic rejection. The ZRR signaling complex reflects a potential therapeutic target for attenuating inflammasome-mediated tissue injury. NLRP3 inflammasomes trigger release of IL-1 to promote tissue injury. Here, Li et al identify a ZFYVE21-Rubicon-RNF34 (ZRR) signaling complex localizing to endosomes and modulating complement-mediated inflammasome activity in vitro and in vivo.

Natural history of atrial and ventricular secondary mitral regurgitation (SMR) is poorly understood. We compared the impact of the degree of SMR on survival between atrial and ventricular dysfunction. We conducted a retrospective cohort study of patients who underwent echocardiography in a healthcare network between 2013-2018. We compared the survival of patients with atrial and ventricular dysfunction, using propensity scores developed from differences in patient demographics and comorbidities within SMR severity strata (none, mild, moderate or severe). We fitted Cox proportional hazards models to estimate the risk-adjusted hazards of death across different severities of SMR between patients with atrial and ventricular dysfunction. Of 11,987 patients included (median age 69 years [IQR 58-80]; 46% women), 6,254 (52%) had isolated atrial dysfunction, and 5,733 (48%) had ventricular dysfunction. 3,522 patients were matched from each arm using coarsened exact matching. Hazard of death in atrial dysfunction without SMR was comparable to ventricular dysfunction without SMR (HR 1.1, 95% CI 0.9-1.3). Using ventricular dysfunction without SMR as reference, hazards of death remained higher in ventricular dysfunction than in atrial dysfunction across increasing severities of SMR: mild SMR (HR 2.1, 95% CI 1.8-2.4 in ventricular dysfunction versus HR 1.7, 95%CI 1.5-2.0 in atrial dysfunction) and moderate/severe SMR (HR 2.8, 95%CI 2.4-3.4 versus HR 2.4, 95%CI 2.0-2.9). SMR across all severities were associated with better survival in atrial dysfunction than in ventricular dysfunction, though the magnitude of the diminishing survival were similar between atrial and ventricular dysfunction in increasing severity of SMRs.

Cardiopulmonary rehabilitation, which often follows major acute cardiac events, is traditionally focused on aerobic exercise and has been associated with decreased morbidity and mortality. Its benefit among cardiac surgery patients is less clear, as is the role of resistance-based exercise programs and their sex-specific effects. This study seeks to evaluate the safety and feasibility of a 12-week resistance training program in patients post cardiac surgery through a sex-specific lens. We conducted a nonrandomized feasibility trial with a 12-week strength training exercise intervention. The primary outcome was safety and feasibility. Secondary outcomes included changes in strength, endurance, and functional capacity; and sex differences among these. Adult participants post open-heart surgery who had completed traditional cardiac rehabilitation were consented. Both patients who completed (cases) or did not complete (controls) a tailored 12-week resistance training program underwent comprehensive assessment of physiologic and physical fitness measures pre- and postintervention. Nine participants enrolled in the trial, including 6 in the intervention arm (median age 61 years; 67% male) and 3 in the control arm (median age 66 years; 67% male). No serious adverse events were noted, indicating safety of the intervention. Participants completed a mean of 34.8/36 (96.7%) of sessions, indicating the feasibility of the program. Although not powered for statistical significance, patients experienced positive trends of improvement in measures of hand grip strength, endurance, and functional capacity with the intervention. When stratified, females experienced greater gains than males in these measures. This proof-of-concept study found that resistance-based exercise after cardiac surgery is well tolerated and feasible. Although all patients experienced improvements in exercise parameters, females reported greater relative improvement than males. •The role of resistance-based exercise programs after cardiac surgery is unclear.•Prior data suggest that women may benefit more than men from exercise.•In this feasibility trial, all participants in a structured strength training program experienced benefits in strength, endurance, and functional capacity.•Women experienced greater gains than men.

In patients with bicuspid aortic valves, guidelines call for regular follow-up to monitor disease progression and guide intervention. We aimed to evaluate how closely these recommendations are followed at a tertiary care center. Among 48,504 patients who received echocardiograms (2013–2018) at a tertiary care center, 245 patients were identified to have bicuspid aortic valve. Bivariate analyses compared characteristics between patients who did and did not receive follow-up by a cardiovascular specialist. During a median follow-up of 3.5 ± 2.2 years (mean age 55.2 ± 15.6 years, 30.2% female), 72.7% of patients had at least one visit with a cardiovascular specialist after diagnosis of bicuspid aortic valve. These patients had a higher proportion of surveillance by echocardiogram (78.7% vs. 34.3%, p < .0001), CT or MRI (41.0% vs. 3.0%, p < .0001), and were more likely to undergo surgery. Patients with moderate-severe valvular or aortic pathology were not more likely to be followed by a specialist or receive follow-up echocardiograms. Follow-up care for patients with bicuspid aortic valve was highly variable, and surveillance imaging was sparse despite guidelines. There is an urgent need for mechanisms to monitor this population with increased risk of progressive valvulopathy and aortopathy.