These data demonstrate that HF increases ObR signalling in cardiomyocytes and that activation of ObR signalling improves functional outcomes in chronic ischaemic injury leading to HF.

BackgroundHypertrophic (HCM) and dilated (DCM) cardiomyopathies result from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca2+ desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis.Methods and FindingsWe ablated Tnnt2 to produce heterozygous Tnnt2 +/− mice, and crossbreeding produced homozygous null Tnnt2 −/− embryos. We also generated transgenic mice overexpressing wildtype (TGWT) or DCM mutant (TGK210Δ) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype (Tnnt2 +/−/TGWT) or mutant (Tnnt2 +/−/TGK210Δ) transgenes. Tnnt2 +/− mice relative to wildtype had significantly reduced transcript (0.82±0.06[SD] vs. 1.00±0.12 arbitrary units; p = 0.025), but not protein (1.01±0.20 vs. 1.00±0.13 arbitrary units; p = 0.44). Tnnt2 +/− mice had normal hearts (histology, mass, left ventricular end diastolic diameter [LVEDD], fractional shortening [FS]). Moreover, whereas Tnnt2 +/−/TGK210Δ mice had severe DCM, TGK210Δ mice had only mild DCM (FS 18±4 vs. 29±7%; p<0.01). The difference in severity of DCM may be attributable to a greater ratio of mutant to wildtype Tnnt2 transcript in Tnnt2 +/−/TGK210Δ relative to TGK210Δ mice (2.42±0.08, p = 0.03). Tnnt2 +/−/TGK210Δ muscle showed Ca2+ desensitization (pCa50 = 5.34±0.08 vs. 5.58±0.03 at sarcomere length 1.9 µm, p<0.01), but no difference in maximum force generation. Day 9.5 Tnnt2 −/− embryos had normally looped hearts, but thin ventricular walls, large pericardial effusions, noncontractile hearts, and severely disorganized sarcomeres.ConclusionsAbsence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype. DCM results from abnormal function of a mutant protein, which is associated with myocyte Ca2+ desensitization. The severity of DCM depends on the ratio of mutant to wildtype Tnnt2 transcript. cTnT is essential for sarcomere formation, but normal embryonic heart looping occurs without contractile activity.

No abstract

The mechanisms by which ␣-adrenergic stimulation of the heart in vivo can cause contractile dysfunction are not well understood. We hypothesized that ␣-adrenergic-mediated contractile dysfunction is mediated through protein kinase C phosphorylation of troponin I, which in in vitro experiments has been shown to reduce actomyosin Mg-ATPase activity. We studied pressure-volume loops in transgenic mice expressing mutant troponin I lacking protein kinase C phosphorylation sites and hypothesized altered responses to phenylephrine. As anesthesia agents can produce markedly different effects on contractility, we studied two agents: avertin and ␣-chloralose-urethane. With ␣-chloralose-urethane, at baseline, there were no contractile abnormalities in the troponin I mutants. Phenylephrine produced a 50% reduction in end-systolic elastance in wild-type controls, although a 9% increase in troponin I mutants (P Ͻ 0.05). Avertin was associated with reduced contractility compared with ␣-chloralose-urethane. Avertin anesthesia, at baseline, produced a reduction in end-systolic elastance by 31% in the troponin I mutants compared with wild-type (P Ͻ 0.05), and this resulted in further marked systolic and diastolic dysfunction with phenylephrine in the troponin I mutants. Dobutamine produced no significant difference in the contractile phenotype of the transgenic mice with either anesthetic regimen. In conclusion, these data (␣-chloralose-urethane) demonstrate that ␣-adrenergic-mediated force reduction is mediated through troponin I protein kinase C phosphorylation. ␤-Adrenergic responses are not mediated through this pathway. Altering the myofilament force-calcium relationship may result in in vivo increased sensitivity to negative inotropy. Thus choice of a negative inotropic anesthetic agent (avertin) with phenylephrine can lead to profound contractile dysfunction.protein kinase C; ventricular function ACUTE ␣-ADRENERGIC STIMULATION of the heart results in several effects, including activation of protein kinase C (3). Potentially, phosphorylation of troponin I by protein kinase C reduces maximal actomyosin Mg-ATPase activity in vitro, which would result in reduction in myofilament force production (15) and negative inotropy. To study the in vivo effects of protein kinase C troponin I phosphorylation, we made a transgenic mouse that expresses mutant troponin I in which the two major protein kinase C phosphorylation sites at serines 43 and 45 were changed to alanine (12). This mouse model does not exhibit any signs of heart failure or hypertrophy and develops and breeds normally. By potentially preserving actomyosin ATPase activity in response to protein kinase C activation, greater force production is predicted. Protein kinase C activation has been achieved with phenylephrine or high perfusate calcium (13,14). In isolated papillary muscle studies, Montgomery et al. (14) demonstrated greater preservation of the force reduction by phenylephrine in the troponin I transgenic mice. In isolated perfused hearts, MacGowan et al. (13) sho...

Objective: Patient-provider communication is a major barrier to care, with some providers giving their personal phone number (PPN) to patients for increased accessibility. We investigated participant utilization of provider’s PPN, its effect on participant satisfaction, provider’s ability to predict abuse of this practice, and evolving provider perceptions. Study Design: Prospective, randomized study. Setting: Single institution, tertiary referral center. Methods: During a 2-week period, otolaryngology patients were randomized to either receive their provider’s PPN or not. Providers predicted the likelihood of abuse. All calls/texts were documented for 4 weeks. At the study’s conclusion, participants were surveyed using Press Ganey metrics. Providers were surveyed before and after to assess their likelihood of providing patients with their PPN and its impact on work demands. Results: Of the 507 participants enrolled, 266 were randomized to the phone number group (+PN). Of 44 calls/texts from 24 participants, 8 were considered inappropriate. Ten participants were predicted to abuse the PPN, but only one was accurately identified. Participants in the +PN group had a greater mean composite satisfaction score than the control group (4.8 vs 4.3; Welch’s t-test, P < .0011). At the conclusion of the study, providers were more likely to share their PPN (Wilcoxon signed-rank test, P < .0313), and their perceived impact of this practice on workload was lower (Wilcoxon signed-rank test, P < .0469). Conclusion: This study demonstrates low patient utilization of provider PPNs, and poor provider predictive ability of patient abuse. Receipt of provider’s PPN was associated with improved patient satisfaction.