Improving the utilization of implantable cardioverter defibrillators for sudden cardiac arrest prevention (Improve SCA) in developing countries: Clinical characteristics and reasons for implantation refusal.

BACKGROUND: Despite available evidence that implantable cardioverter defibrillators (ICDs) reduce all-cause mortality among patients at risk for sudden cardiac death, utilization of ICDs is low especially in developing countries. OBJECTIVE: To summarize reasons for ICD or cardiac resynchronization therapy defibrillator implant refusal by patients at risk for sudden cardiac arrest (Improve SCA) in developing countries. METHODS: Primary prevention (PP) and secondary prevention (SP) patients from countries where ICD use is low were enrolled. PP patients with additional risk factors (syncope, ejection fraction < 25%, nonsustained ventricular tachycardia [NSVT], or frequent premature ventricular complexes) were further categorized as "1.5 PP patients." Candidates who declined implantation were asked for reasons for refusal. Baseline factors that may have influenced the implant decision were examined using logistic regression. RESULTS: Among 3892 patients, the implant refusal rate was 46.5% among PP patients (n = 2700), and 10.3% among SP patients (n = 1192). The most common refusal reason was inability to pay for the device (53.8%), followed by not believing in the benefits of the ICD (19.4%). Among PP ICD candidates, those with no syncope, no NSVT, no premature ventricular contractions, shorter QRS duration, no atrial arrhythmias, and no left bundle branch block were more likely to refuse implant. Among SP candidates, a history of cardiovascular surgery and no sinus node dysfunction were significant predictors of ICD refusal. Additionally, countries had significant differences in patient refusal rates among PP and SP groups. CONCLUSION: Implant refusal among PP patients is high in many countries. Increased reimbursement and better awareness of the benefits of an ICD could increase their utilization.

Colonic transcriptional response to 1α,25(OH)2 vitamin D3 in African- and European-Americans.

Colorectal cancer (CRC) is a significant health burden especially among African Americans (AA). Epidemiological studies have correlated low serum vitamin D with CRC risk, and, while hypovitaminosis D is more common and more severe in AA, the mechanisms by which vitamin D modulates CRC risk and how these differ by race are not well understood. Active vitamin D (1α,25(OH)2D3) has chemoprotective effects primarily through transcriptional regulation of target genes in the colon. We hypothesized that transcriptional response to 1α,25(OH)2D3 differs between AA and European Americans (EA) irrespective of serum vitamin D and that regulatory variants could impact transcriptional response. We treated ex vivo colon cultures from 34 healthy subjects (16 AA and 18 EA) with 0.1µM 1α,25(OH)2D3 or vehicle control for 6h and performed genome-wide transcriptional profiling. We found 8 genes with significant differences in transcriptional response to 1α,25(OH)2D3 between AA and EA with definitive replication of inter-ethnic differences for uridine phosphorylase 1 (UPP1) and zinc finger-SWIM containing 4 (ZSWIM4). We performed expression quantitative trait loci (eQTL) mapping and identified response cis-eQTLs for ZSWIM4 as well as for histone deacetylase 3 (HDAC3), the latter of which showed a trend toward significant inter-ethnic differences in transcriptional response. Allele frequency differences of eQTLs for ZSWIM4 and HDAC3 accounted for observed transcriptional differences between populations. Taken together, our results demonstrate that transcriptional response to 1α,25(OH)2D3 differs between AA and EA independent of serum 25(OH)D levels. We provide evidence in support of a genetic regulatory mechanism underlying transcriptional differences between populations for ZSWIM4 and HDAC3. Further work is needed to elucidate how response eQTLs modify vitamin D response and whether genotype and/or transcriptional response correlate with chemopreventive effects. Relevant biomarkers, such as tissue-specific 1α,25(OH)2D3 transcriptional response, could identify individuals likely to benefit from vitamin D for CRC prevention as well as elucidate basic mechanisms underlying CRC disparities.