Publications

Activin like kinase-1 (AlK-1) mediates signaling via the transforming growth factor beta (TGFβ) family of ligands. AlK-1 activity promotes endothelial proliferation and migration. Reduced AlK-1 activity is associated with arteriovenous malformations. No studies have examined the effect of global AlK-1 deletion on indices of cardiac remodeling. We hypothesized that reduced levels of AlK-1 promote maladaptive cardiac remodeling. To test this hypothesis, we employed AlK-1 conditional knockout mice (cKO) harboring the ROSA26-CreER knock-in allele, whereby a single dose of intraperitoneal tamoxifen triggered ubiquitous Cre recombinase-mediated excision of floxed AlK-1 alleles. Tamoxifen treated wild-type (WT-TAM; n = 5) and vehicle treated AlK-1-cKO mice (cKO-CON; n = 5) served as controls for tamoxifen treated AlK-1-cKO mice (cKO-TAM; n = 15). AlK-1 cKO-TAM mice demonstrated reduced 14-day survival compared to cKO-CON controls (13 vs 100%, respectively, p < 0.01). Seven days after treatment, cKO-TAM mice exhibited reduced left ventricular (LV) fractional shortening, progressive LV dilation, and gastrointestinal bleeding. After 14 days total body mass was reduced, but LV and lung mass increased in cKO-TAM not cKO-CON mice. Peak LV systolic pressure, contractility, and arterial elastance were reduced, but LV end-diastolic pressure and stroke volume were increased in cKO-TAM, not cKO-CON mice. LV AlK-1 mRNA levels were reduced in cKO-TAM, not cKO-CON mice. LV levels of other TGFβ-family ligands and receptors (AlK5, TBRII, BMPRII, Endoglin, BMP7, BMP9, and TGFβ1) were unchanged between groups. Cardiomyocyte area and LV levels of BNP were increased in cKO-TAM mice, but LV levels of β-MHC and SERCA were unchanged. No increase in markers of cardiac fibrosis, Type I collagen, CTGF, or PAI-1, were observed between groups. No differences were observed for any variable studied between cKO-CON and WT-TAM mice. Global deletion of AlK-1 is associated with the development of high output heart failure without maladaptive remodeling. Future studies exploring the functional role of AlK-1 in cardiac remodeling independent of systemic AVMs are required.

BACKGROUND

Depression among patients with acute myocardial infarction (AMI) is prevalent and associated with an adverse quality of life and prognosis. Despite recommendations from some national organizations to screen for depression, it is unclear whether treatment of depression in patients with AMI is associated with better outcomes. We aimed to determine whether the prognosis of patients with treated versus untreated depression differs.

METHODS

The TRIUMPH study (Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status) is an observational multicenter cohort study that enrolled 4062 patients aged ≥18 years with AMI between April 11, 2005, and December 31, 2008, from 24 US hospitals. Research coordinators administered the Patient Health Questionnaire-9 (PHQ-9) during the index AMI admission. Depression was defined by a PHQ-9 score of ≥10. Depression was categorized as treated if there was documentation of a discharge diagnosis, medication prescribed for depression, or referral for counseling, and as untreated if none of these 3 criteria was documented in the medical records despite a PHQ score ≥10. One-year mortality was compared between patients with AMI having: (1) no depression (PHQ-9<10; reference); (2) treated depression; and (3) untreated depression adjusting for demographics, AMI severity, and clinical factors.

RESULTS

Overall, 759 (18.7%) patients met PHQ-9 criteria for depression and 231 (30.4%) were treated. In comparison with 3303 patients without depression, the 231 patients with treated depression had 1-year mortality rates that were not different (6.1% versus 6.7%; adjusted hazard ratio, 1.12; 95% confidence interval, 0.63-1.99). In contrast, the 528 patients with untreated depression had higher 1-year mortality in comparison with patients without depression (10.8% versus 6.1%; adjusted hazard ratio, 1.91; 95% confidence interval, 1.39-2.62).

CONCLUSIONS

Although depression in patients with AMI is associated with increased long-term mortality, this association may be confined to patients with untreated depression.