The calcium, calmodulin-dependent phosphatase calcineurin, regulates growth and gene expression of striated muscles. The activity of calcineurin is modulated by a family of cofactors, referred to as modulatory calcineurin-interacting proteins (MCIPs). In the heart, the MCIP1 gene is activated by calcineurin and has been proposed to fulfill a negative feedback loop that restrains potentially pathological calcineurin signaling, which would otherwise lead to abnormal cardiac growth. In a high-throughput screen for small molecules capable of regulating MCIP1 expression in muscle cells, we identified a unique 4-aminopyridine derivative exhibiting an embedded partial structural motif of serotonin (5-hydroxytryptamine, 5-HT). This molecule, referred to as pyridine activator of myocyte hypertrophy, acts as a selective agonist for 5-HT2A/2B receptors and induces hypertrophy of cardiac muscle cells through a signaling pathway involving calcineurin and a kinase-dependent mechanism that inactivates class II histone deacetylases, which act as repressors of cardiac growth. 2). Activation of the calcium, calmodulin-dependent phosphatase calcineurin, is sufficient and, in many cases, necessary for pathological cardiac hypertrophy (3), a major predictor of human morbidity and mortality (4). Thus, there has been intense interest in identifying novel small molecules capable of therapeutically modulating cardiac calcineurin signaling.Many calcineurin-sensitive genes are controlled by members of the nuclear factor of activated T-cell (NFAT) family of transcription factors, which translocate to the nucleus when dephosphorylated by calcineurin (reviewed in ref. 5). The calcineurin pathway also stimulates the myocyte enhancer factor-2 (MEF2) transcription factor by multiple mechanisms (6). We have shown that calcineurin activates a kinase that phosphorylates class II histone deacetylases (HDACs), which act as MEF2 corepressors (7). Signal-dependent phosphorylation of class II HDACs triggers their export from the nucleus and activation of MEF2 target genes (8, 9). HDAC mutants lacking the signalresponsive phosphorylation sites are refractory to calcium signaling and prevent cardiomyocyte hypertrophy. Conversely, mice lacking class II HDACs are hypersensitive to the growthpromoting activity of calcineurin (7).The activity of calcineurin is influenced by cofactors known as modulatory calcineurin-interacting proteins (MCIPs) or calcipressins (reviewed in ref. 10). Recent studies in yeast (11) and mammalian cells (12-14) have revealed both positive and negative roles for these proteins in the control of calcineurin activity. Overexpression of MCIP1 (also called Down syndrome critical region 1), for example, suppresses calcineurin signaling (12). In contrast, MCIP1 also seems to potentiate calcineurin signaling, as demonstrated by the diminution of calcineurin activity in the hearts of MCIP1 knockout mice (13). Intriguingly, the MCIP1 gene is a target of NFAT and is up-regulated in response to calcineurin signaling (15), which has been propo...
Background Acute type A aortic dissection (ATAAD) is a surgical emergency with an operative mortality of up to 30%, a rate which has not changed meaningfully in over two decades. A growing body of research has highlighted several comorbidities and presenting factors in which delay or permanent deferral of surgery may be considered; however, modern comprehensive summative reviews are lacking. The urgency and timing of this review are underscored by significant challenges in resource utilization posed by the COVID-19 pandemic. This review provides an update on the current understanding of risk assessment, surgical candidacy, and operative timing in patients with ATAAD. Methods A literature search was conducted through PubMed and Embase databases to identify relevant studies relating to risk assessment in ATAAD. Articles were selected via group consensus based on quality and relevance. Results Several patient factors have been identified which increase risk in ATAAD repair. In particular, frailty, advanced age, prior cardiac surgery, and use of novel anticoagulant medications have been studied. The understanding of malperfusion syndromes has also expanded significantly, including recommendations for surgical delay. Finally, approaches to triage have been significantly influenced by resource limitations related to the ongoing COVID-19 pandemic. While medical management remains a reasonable option in carefully selected patients at prohibitive risk for open surgery, endovascular therapies for treatment of ATAAD are rapidly evolving. Conclusions Early surgical repair remains the preferred treatment for most patients with ATAAD, however, improvements in risk stratification should guide appropriate delay or permanent deferral of surgery in select individuals.
Thoracic endovascular aortic repair (TEVAR) of the ascending aorta is a developing alternative treatment strategy, which currently is specifically aimed at patients who are too high risk for open surgery. TEVAR has been applied to patients with a variety of pathologies of the ascending aorta including type A dissection, intramural hematoma (IMH), penetrating ulcers, aneurysm and pseudoaneurysm. Here we discuss the current evidence regarding the use of TEVAR for the ascending aorta as well as the latest techniques and pitfalls of the procedure. The challenges of this modality are considerable, and the techniques that have been applied draw from the many facets of endovascular experience. There is limited literature regarding the use of stent grafts in the ascending aorta, and the pool of patients currently considered appropriate candidates for the procedure is small. This is an evolving intervention that warrants further study and the development of devices specifically engineered to meet the anatomical and physiologic challenges of the ascending aorta.
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