A human polymorphism of protein phosphatase-1 inhibitor-1 is associated with attenuated contractile response of cardiomyocytes to beta-adrenergic stimulation.

Aberrant beta-adrenergic signaling and depressed calcium homeostasis, associated with an imbalance of protein kinase A and phosphatase-1 activities, are hallmarks of heart failure. Phosphatase-1 is restrained by its endogenous inhibitor, protein phosphatase inhibitor-1 (PPI-1). We assessed 352 normal subjects, along with 959 patients with heart failure and identified a polymorphism in PPI-1 (G147D) exclusively in black subjects. To determine whether the G147D variant could affect cardiac function, we infected adult cardiomyocytes with adenoviruses expressing D147 or wild-type (G147) PPI-1. Under basal conditions, there were no significant differences in fractional shortening or contraction or relaxation rates. However, the enhancement of contractile parameters after isoproterenol stimulation was significantly blunted in D147 compared with G147 and control myocytes. Similar findings were observed in calcium kinetics. The attenuated beta-agonist response was associated with decreased (50%) phosphorylation of phospholamban (PLN) at serine 16, whereas phosphorylation of troponin I and ryanodine receptor was unaltered. These findings suggest that the human G147D PPI-1 can attenuate responses of cardiomyocytes to beta-adrenergic agonists by decreasing PLN phosphorylation and therefore may contribute to deteriorated function in heart failure.

Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction.

OBJECTIVES: The aim of this study was to evaluate the prevalence and prognostic impacts of noncardiac comorbidities in patients with heart failure (HF) with preserved ejection fraction (HFpEF) compared with those with HF with reduced ejection fraction (HFrEF). BACKGROUND: There is a paucity of information on the comparative prognostic significance of comorbidities between patients with HFpEF and those with HFrEF. METHODS: In a national ambulatory cohort of veterans with HF, the comorbidity burden of 15 noncardiac comorbidities and the impacts of these comorbidities on hospitalization and mortality were compared between patients with HFpEF and those with HFrEF. RESULTS: The cohort consisted of 2,843 patients with HFpEF and 6,599 with HFrEF with 2-year follow-up. Compared with patients with HFrEF, those with HFpEF were older and had higher prevalence of chronic obstructive pulmonary disease, diabetes, hypertension, psychiatric disorders, anemia, obesity, peptic ulcer disease, and cancer but a lower prevalence of chronic kidney disease. Patients with HFpEF had lower HF hospitalization, higher non-HF hospitalization, and similar overall hospitalization compared with those with HFrEF (p < 0.001, p < 0.001, and p = 0.19, respectively). An Increasing number of noncardiac comorbidities was associated with a higher risk for all-cause admissions (p < 0.001). Comorbidities had similar impacts on mortality in patients with HFpEF compared with those with HFrEF, except for chronic obstructive pulmonary disease, which was associated with a higher hazard (1.62 [95% confidence interval: 1.36 to 1.92] vs. 1.23 [95% confidence interval: 1.11 to 1.37], respectively, p = 0.01 for interaction) in patients with HFpEF. CONCLUSIONS: There is a higher noncardiac comorbidity burden associated with higher non-HF hospitalizations in patients with HFpEF compared with those with HFrEF. However, individually, most comorbidities have similar impacts on mortality in both groups. Aggressive management of comorbidities may have an overall greater prognostic impact in HFpEF compared to HFrEF.