ABSTRACT
Background: Atrial fibrillation (AF) is the most common arrhythmia with a growing prevalence worldwide, especially in the elderly population. Patients with AF are at higher risk of serious life-threatening events and complications that may lead to long-term sequelae and reduce quality of life. The aim of our study was to examine the association of additional risk factors and comorbid medical conditions with AF in patients 65 years, or older. Methods: We performed a retrospective electronic medical record review of patients aged 65 years and older, who visited our internal medicine office between July 1, 2020 and June 30, 2021. Results: Among 2,433 patients, 418 patients (17.2%) had AF. Our analysis showed that for each unit increased in age, there was a 4.5% increase in the odds of AF (95% confidence interval (CI) 2.2-6.9%; P < 0.001). Compared to patients of Caucasian descent, African-American patients had significantly decreased odds of AF (odds ratio (OR) 0.274, 95% CI 0.141 - 0.531; P < 0.001). Patients with hypertension had 2.241 greater odds of AF (95% CI 1.421 - 3.534; P = 0.001). Additional comorbidities with significantly greater odds of AF included other cardiac arrhythmias (OR 2.523, 95% CI 1.720 - 3.720; P < 0.001), congestive heart failure (OR 3.111, 95% CI 1.674 - 5.784; P < 0.001), osteoarthritis (OR 3.014, 95% CI 2.138 - 4.247; P < 0.001), liver disease (OR 2.129, 95% CI 1.164 - 3.893; P = 0.014), and colorectal disease (OR 1.500 95% CI 1.003 - 2.243; P = 0.048). Comorbidities with significantly decreased odds of AF included other rheumatological disorder (OR 0.144, 95% CI 0.086 - 0.243; P < 0.001), non-steroidal anti-inflammatory drugs (NSAIDs) use (OR 0.206, 95% CI 0.125 - 0.338; P < 0.001), and corticosteroid use (OR 0.553, 95% CI 0.374 - 0.819; P = 0.003). Conclusions: Increasing age, hypertension, presence of other cardiac arrhythmias, congestive heart failure, osteoarthritis, liver disease, and colorectal disease are associated with increased odds of having AF.
ABSTRACT
BACKGROUND: Recent studies have shown that bone morphogenetic protein receptor 2 (BMPR2) regulates cell survival signaling events in cancer cells independent of the BMP type 1 receptor (BMPR1) or the Smad-1/5 transcription factor. Mutations in BMPR2 trafficking proteins leads to overactive BMP signaling, which leads to neurological diseases caused by BMPR2 stabilization of the microtubules. It is not known whether BMPR2 regulates the microtubules in cancer cells and what effect this has on cell survival. It is also not known whether alterations in BMPR2 trafficking effects activity and response to BMPR2 inhibitors. METHODS: We utilized BMPR2 siRNA and the BMP receptor inhibitors JL5 and Ym155, which decrease BMPR2 signaling and cause its mislocalization to the cytoplasm. Using the JL5 resistant MDA-MD-468 cell line and sensitive lung cancer cell lines, we examined the effects of BMPR2 inhibition on BMPR2 mislocalization to the cytoplasm, microtubule destabilization, lysosome activation and cell survival. RESULTS: We show that the inhibition of BMPR2 destabilizes the microtubules. Destabilization of the microtubules leads to the activation of the lysosomes. Activated lysosomes further decreases BMPR2 signaling by causing it to mislocalizated to the cytoplasm and/or lysosome for degradation. Inhibition of the lysosomes with chloroquine attenuates BMPR2 trafficking to the lysosome and cell death induced by BMPR2 inhibitors. Furthermore, in MDA-MD-468 cells that are resistant to JL5 induced cell death, BMPR2 was predominately located in the cytoplasm. BMPR2 failed to localize to the cytoplasm and/or lysosome following treatment with JL5 and did not destabilize the microtubules or activate the lysosomes. CONCLUSIONS: These studies reveal that the inhibition of BMPR2 destabilizes the microtubules promoting cell death of cancer cells that involves the activation of the lysosomes. Resistance to small molecules targeting BMPR2 may occur if the BMPR2 is localized predominantly to the cytoplasm and/or fails to localize to the lysosome for degradation. Video Abstract.
