17phosphorylation by CaMKII and is essential to the relaxant effect of -adrenergic stimulation. To determine the role of Thr 17 PLB phosphorylation, we investigated the dual-site phosphorylation of PLB in isolated adult rat cardiac myocytes in response to  1 -adrenergic stimulation or electrical field stimulation (0.1-3 Hz) or both. A  1 -adrenergic agonist, norepinephrine (10 ؊9 -10 (1-3). In the beating mammalian heart, -adrenergic stimulation increases both PKA-and CaMKIImediated phosphorylation of Ser 16 and Thr 17 (4 -6). More recent studies have shown that the effects of -adrenergic stimulation on PLB phosphorylation are mostly attributable to  1 -but not  2 -adrenergic receptor subtype (7-10).Over the last two decades, intensive studies have been focused on the physiological significance of the dual site phosphorylation of PLB. These previous studies in perfused hearts or in vivo have provided several lines of evidence leading to the concept that Ser 16 phosphorylation is a prerequisite for phosphorylation of Thr 17 and that Ser 16 phosphorylation is largely responsible for -adrenergic modulation of cardiac relaxation (4, 5, 11, 12, 14 -18 phosphorylation is the dominant molecular event responsible for accelerated cardiac relaxation. However, in vitro studies in the isolated SR membranes have consistently indicated that Ser 16 and Thr 17 can be readily and independently phosphorylated by PKA and CaMKII, respectively, and that when both are phosphorylated, there is an additive interaction (20,21). The apparent discrepancy between in vivo and in vitro PLB phosphorylation is yet to be reconciled.To resolve this paradox and to further address the relative contribution of PKA-and CaMKII-mediated PLB phosphorylation in beat-to-beat cardiac functional modulation, individually we manipulated PKA activity, using -adrenergic stimulation in quiescent rat ventricular myocytes, and CaMKII activity, by electrically pacing the myocytes at different stimulation frequency (0.1-3 Hz) in the absence of -adrenergic stimulation. Both stimuli were also combined to explore possible interactions between PKA-and CaMKII-mediated signaling. Under those experimental conditions, we measured PLB phosphorylation at Ser 16 and Thr 17 as well as relaxation time of cell contraction. Here, we report our surprising findings that electrical stimulation alone increases CaMKII-dependent phosphorylation of PLB at Thr 17 in a frequency-dependent manner without altering PKA-mediated Ser 16 phosphorylation, that phosphorylation of Thr 17 is markedly enhanced by -adrenergic stimulation in the electrically paced but not in quiescent myocytes, and that Thr 17 phosphorylation is associated with a significant relaxant effect, regardless of -adrenergic stimulation.
The period following heart failure hospitalization (HFH) is a vulnerable time with high rates of death or recurrent HFH.OBJECTIVE To evaluate clinical characteristics, outcomes, and treatment response to vericiguat according to prespecified index event subgroups and time from index HFH in the Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) trial. DESIGN, SETTING, AND PARTICIPANTSAnalysis of an international, randomized, placebo-controlled trial. All VICTORIA patients had recent (<6 months) worsening HF (ejection fraction <45%). Index event subgroups were less than 3 months after HFH (n = 3378), 3 to 6 months after HFH (n = 871), and those requiring outpatient intravenous diuretic therapy only for worsening HF (without HFH) in the previous 3 months (n = 801). Data were analyzed between May 2, 2020, and May 9, 2020.INTERVENTION Vericiguat titrated to 10 mg daily vs placebo. MAIN OUTCOMES AND MEASURESThe primary outcome was time to a composite of HFH or cardiovascular death; secondary outcomes were time to HFH, cardiovascular death, a composite of all-cause mortality or HFH, all-cause death, and total HFH. RESULTS Among 5050 patients in the VICTORIA trial, mean age was 67 years, 24% were women, 64% were White, 22% were Asian, and 5% were Black. Baseline characteristics were balanced between treatment arms within each subgroup. Over a median follow-up of 10.8 months, the primary event rates were 40.9, 29.6, and 23.4 events per 100 patient-years in the HFH at less than 3 months, HFH 3 to 6 months, and outpatient worsening subgroups, respectively. Compared with the outpatient worsening subgroup, the multivariable-adjusted relative risk of the primary outcome was higher in HFH less than 3 months (adjusted hazard ratio, 1.48; 95% CI, 1.27-1.73), with a time-dependent gradient of risk demonstrating that patients closest to their index HFH had the highest risk. Vericiguat was associated with reduced risk of the primary outcome overall and in all subgroups, without evidence of treatment heterogeneity. Similar results were evident for all-cause death and HFH. Addtionally, a continuous association between time from HFH and vericiguat treatment showed a trend toward greater benefit with longer duration since HFH. Safety events (symptomatic hypotension and syncope) were infrequent in all subgroups, with no difference between treatment arms.CONCLUSIONS AND RELEVANCE Among patients with worsening chronic HF, those in closest proximity to their index HFH had the highest risk of cardiovascular death or HFH, irrespective of age or clinical risk factors. The benefit of vericiguat did not differ significantly across the spectrum of risk in worsening HF.
IMPORTANCE Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients. OBJECTIVE To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient's lifetime.DESIGN, SETTING, AND PARTICIPANTS Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months.INTERVENTIONS Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy. MAIN OUTCOMES AND MEASURESThe primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient's lifetime for the primary outcome and the secondary outcome of death from any cause.RESULTS A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival. CONCLUSIONS AND RELEVANCEThese findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03036124
1. The effects of doxorubicin (DOX) on intracellular calcium transients were examined in neonatal rat cultured cardiac myocytes, as were the cardioprotective effects of an angiotensin-converting enzyme (ACE) inhibitor on DOX-induced impairment of calcium handling. 2. Cultured cardiac myocytes isolated from neonatal Wistar-Kyoto rats were treated with DOX for 24 h. Field-stimulated calcium transients in single myocytes were measured in the presence or in the absence of isoproterenol using fura-2/AM. Calcium transients were also measured after the addition of DOX to myocytes pretreated with M-I (an active metabolite of delapril HCL, an ACE inhibitor. 3. Doxorubicin reduced the amplitude and maximum velocity of increase and decrease of calcium transients, prolonged the time-course of calcium transients and impaired the beta-adrenoceptor responsiveness of calcium transients in a dose-dependent manner. The DOX-induced impairment of calcium transients and beta-adrenoceptor responsiveness was improved by M-I. 4. Doxorubicin impaired both the mobilization and sequestration of intracellular calcium ions in contraction-relaxation cycles and the response of calcium transients to beta-adrenoceptor stimulation. The ACE inhibitor ameliorated DOX-induced impairment of calcium dynamics, suggesting ihat M-I, an active metabolite of delapril, protects against DOX-induced abnormal calcium handling leading to cardiac dysfunction.
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