SUMMARY Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glucogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome.

The vascular smooth muscle cell (SMC)-specific isoform of alpha-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD. Sequencing of DNA from patients with nonfamilial TAAD and from premature-onset CAD patients independently identified ACTA2 mutations in these patients and premature onset strokes in family members with ACTA2 mutations. Vascular pathology and analysis of explanted SMCs and myofibroblasts from patients harboring ACTA2 suggested that increased proliferation of SMCs contributed to occlusive diseases. These results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD. These data demonstrate that diffuse vascular diseases resulting from either occluded or enlarged arteries can be caused by mutations in a single gene and have direct implications for clinical management and research on familial vascular diseases.

Repairing thoracoabdominal aortic aneurysms poses substantial risks, particularly when the entire thoracoabdominal aorta (extent II) is replaced. Nonetheless, our data suggest that thoracoabdominal aortic aneurysm repair, when performed at an experienced center, can produce respectable outcomes.

Perioperative CSFD reduces the rate of paraplegia after repair of extent I and II TAAAs.

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-Atrial fibrillation (AF) is frequently associated with enhanced inflammatory response. The "NACHT, LRR and PYD domain containing protein 3" (NLRP3)-inflammasome mediates caspase-1 activation and interleukin-1β release in immune cells, but is not known to play a role in cardiomyocytes (CMs). Here, we assessed the role of CM NLRP3-inflammasome in AF. -NLRP3-inflammasome activation was assessed by immunoblot in atrial whole-tissue lysates and CMs from patients with paroxysmal (pAF) or long-standing persistent (chronic) AF (cAF). To determine whether CM-specific activation of NLPR3 is sufficient to promote AF, a CM-specific knock-in mouse model expressing constitutively active NLRP3 (CM-KI) was established. In vivo electrophysiology was used to assess atrial arrhythmia vulnerability. To evaluate the mechanism of AF, electrical activation pattern, Ca spark frequency (CaSF), atrial effective refractory period (AERP), and morphology of atria were evaluated in CM-KI mice and WT littermates. -NLRP3-inflammasome activity was increased in atrial CMs of pAF and cAF patients. CM-KI mice developed spontaneous premature atrial contractions and inducible AF, which was attenuated by a specific NLRP3-inflammasome inhibitor, MCC950. CM-KI mice exhibited ectopic activity, abnormal sarcoplasmic-reticulum Ca-release, AERP shortening and atrial hypertrophy. Adeno-associated virus subtype-9 mediated CM-specific knockdown of suppressed AF development in CM-KI mice. Finally, genetic inhibition of prevented AF development in CREM transgenic mice, a well-characterized mouse model of spontaneous AF. -Our study establishes a novel pathophysiological role for CM NLRP3-inflammasome signaling with a mechanistic link to the pathogenesis of AF, and establishes inhibition of NLRP3 as a potential novel AF-therapy approach.

PREAMBLEOur mission was to develop evidence-based American Association for Thoracic Surgery (AATS) consensus focused on the surgical treatment of infective endocarditis (IE) and perioperative questions: when to operate, how to prepare the patient for operation, how to operate, and other issues relevant to managing and following patients after surgery. [1][2][3][4][5][6][7][8] The writing committee included 4 cardiac surgeons, 1 cardiologist, 2 infectious disease specialists, and Dr Eugene H. Blackstone. The draft produced was reviewed by invited additional experts, including 4 cardiac surgeons, 1 anesthesiologist, 1 cardiologist, 2 imaging experts, 3 infectious disease specialists, and 1 neurologist (See Appendix E1).

Thoracic aortic dissection (TAD) is estimated to occur at a rate of 3-4 cases per 100,000 persons per year and is associated with a high mortality. Reported rates are probably underestimates of the true incidence of TAD because of difficulties in diagnosis. The incidence of TAD appears to have been increasing over time. TAD is most common in men and older individuals. Aortic dilatation is a well-established risk factor for TAD but is not a prerequisite; most ascending aortic dissections occur when aortic diameter is <5.5 cm. Although atherosclerosis and typical cardiovascular risk factors, such as hypertension and smoking, are associated with TAD, evidence supporting their direct causal role is lacking. Notably, diabetes mellitus is remarkably uncommon in patients with TAD. Other risk factors for TAD include inflammatory diseases, iatrogenic aortic injury, and drug use. Congenital cardiovascular defects, such as bicuspid aortic valve, and certain genetic syndromes, such as Marfan syndrome, are the genetic factors most commonly associated with TAD. Specific nonsyndromic genetic mutations in families and single nucleotide polymorphisms have also been identified as possible risk factors for TAD.