Muscarinic type-1 receptors contribute to IK,ACh in human atrial cardiomyocytes and are upregulated in patients with chronic atrial fibrillation.

BACKGROUND: Basal and acetylcholine-gated inward-rectifier K+-currents (IK1 and IK,ACh, respectively) are altered in atrial fibrillation (AF). Gi-protein-coupled muscarinic (M) receptors type-2 are considered the predominant receptors activating IK,ACh. Although a role for Gq-coupled non-M2-receptor subtypes has been suggested, the precise regulation of IK,ACh by multiple M-receptor subtypes in the human atrium is unknown. Here, we investigated M1-receptor-mediated IK,ACh regulation and its remodeling in chronic AF (cAF). METHODS AND RESULTS: M1-receptor mRNA and protein abundance were increased in atrial cardiomyocyte fractions and atrial homogenates from cAF patients, whereas M2-receptor levels were unchanged. The regulation of IK,ACh by M1-receptors was investigated in right-atrial cardiomyocytes using two applications of the M-receptor agonist carbachol (CCh, 2µM), with pharmacological interventions during the second application. CCh application produced a rapid current increase (Peak-IK,ACh), which declined to a quasi-steady-state level (Qss-IK,ACh). In sinus rhythm (Ctl) the selective M1-receptor antagonists pirenzepine (10nM) and muscarinic toxin-7 (MT-7, 10nM) significantly inhibited CCh-activated Peak-IK,ACh, whereas in cAF they significantly reduced both Peak- and Qss-IK,ACh, with no effects on basal inward-rectifier currents in either group. Conversely, the selective M1-receptor agonist McN-A-343 (100µM) induced a current similar to the CCh-activated current in Ctl atrial cardiomyocytes pretreated with pertussis toxin to inhibit M2-receptor-mediated Gi-protein signaling, which was abolished by MT-7. Computational modeling indicated that M1- and M2-receptors redundantly activate IK,ACh to abbreviate APD, albeit with predominant effects of M2-receptors. CONCLUSION: Our data suggest that Gq-coupled M1-receptors also regulate human atrial IK,ACh and that their relative contribution to IK,ACh activation is increased in cAF patients. We provide novel insights about the role of non-M2-receptors in human atrial cardiomyocytes, which may have important implications for understanding AF pathophysiology.

Subarachnoid Hemorrhage in Advanced Age: Comparison of Patients Aged 70-79 Years and 80 Years and Older.

BACKGROUND: Clinical routine shows an increasing admission rate of elderly patients suffering from subarachnoid hemorrhage (SAH). OBJECTIVE: Aim of the study was to identify differences in outcome and prognostic factors to better anticipate clinical course and therefore treat this special subgroup better. METHODS: We retrospectively compared patients aged 70-79 and older than 80 years (80+). Patients were entered into a prospectively collected database. Between 1999 and June 2014, 191 patients aged ≥70 years suffered from SAH. We stratified between patients aged from 70 to 79 years (n = 138) and 80+ years (n = 53). Outcome was assessed by modified Rankin Scale 6 months after SAH. RESULTS: During the observation period, the rate of elderly patients increased from 9% to 24%. Patients aged 80+ years less often showed significant early hydrocephalus, cerebral vasospasm, and shunt dependence. A total of 51% of all patients were treated by coiling, whereupon also treatment modality had no influence on outcome. By comparing clinical outcomes, no significant differences could be detected. However, mortality rate was not significantly greater in patients 80+ years. Clinical status at time of admission statistically was a prognostic factor in elderly patients as well as the extent of blood clots and an early hydrocephalus. Patients aged 80+ years suffered less from severe cerebral vasospasm, which statistically was no prognostic factor for a favorable outcome in this group. CONCLUSIONS: Patients aged 80+ years with SAH also can achieve a favorable outcome. There was no difference in clinical outcome comparing both groups, but several pathophysiological mechanisms in elderly patients (especially 80+ years) seem to have a positive influence on typical complications after SAH, such as cerebral vasospasm, early hydrocephalus, and shunt dependence.

Acute lymphoblastic leukemia with low hypodiploid/near triploid karyotype is a specific clinical entity and exhibits a very high TP53 mutation frequency of 93%.

B lymphoblastic leukemia/lymphoma (ALL) are subdivided by the WHO classification into five subgroups defined by specific translocations and two further subgroups defined by the number of chromosomes. The hypodiploid subgroup is heterogeneous and comprises ALL with a chromosome number of <46. To characterize a specific subset with low hypodiploid karyotype, we performed chromosome banding analysis, FISH, array comparative genomic hybridization, and mutational analyses of FBXW7, NOTCH1, KRAS, NRAS, TP53, and IKZF1 in 29 cases. We observed a nonrandom pattern of chromosome losses, including chromosomes 3, 7, 13, 15, 16, and 17. A deletion encompassing the CDKN2A/B locus was the only recurrent structural abnormality. A duplication of the low hypodiploid karyotype occurred frequently, resulting in a near triploid karyotype based on the definition by merely counting chromosomes but in fact was a very low tetraploid chromosome set. Mutational analyses revealed no mutations in IKZF1, FBXW7, NOTCH1, and KRAS and only one mutation in NRAS. However, we discovered a high frequency of TP53 mutations in 93% (27/29) of cases. In 26/27 cases with TP53 mutation, the second TP53 allele was lost due to monosomy 17. Median overall survival was short (18.5 months), which might be related to the high frequency of TP53 alterations. Therefore, ALL with low hypodiploidy is characterized by a typical pattern of chromosome losses and a remarkably high TP53 mutation frequency. Our data suggest the introduction of a novel WHO entity within the B lymphoblastic leukemia/lymphoma group showing low hypodiploid/very low tetraploid karyotype and concomitant TP53 mutation.