Significant reduction in heart rate variability is a feature of acute decompensation of cirrhosis and predicts 90-day mortality

Background: Heart rate variability (HRV) is reduced in cirrhosis and in conditions of systemic inflammation. Whether HRV is associated with cirrhosis decompensation and development of acute‐on‐chronic liver failure (ACLF) is unknown. // Aims: To (a) validate wireless remote HRV monitoring in cirrhosis decompensation; (b) determine if severely reduced HRV is a surrogate for inflammation and progression of cirrhosis decompensation; (c) assess if measuring HRV determines prognosis in cirrhosis decompensation. // Methods: One hundred and eleven patients at risk of cirrhosis decompensation at two clinical sites were monitored for HRV. Standard deviation of all normal beat‐beat intervals (SDNN) reflecting HRV was assessed using remote monitoring (Isansys Lifetouch) and/or Holter ECG recording. Clinical outcomes and major prognostic scores were recorded during 90‐day follow‐up. // Results: Reduced HRV denoted by lower baseline SDNN, correlated with severity of decompensation (median 14 (IQR 11‐23) vs 33 (25‐42); P < 0.001, decompensated patients vs stable outpatient cirrhosis). Furthermore, SDNN was significantly lower in patients developing ACLF compared to those with only decompensation (median 10 (IQR9‐12) vs 16 (11‐24); P = 0.02), and correlated inversely with MELD and Child‐Pugh scores, and C‐reactive protein (all P < 0.0001) and white cell count (P < 0.001). SDNN predicted disease progression on repeat measures and appeared an independent predictor of 90‐day mortality (12 patients). An SDNN cut‐off of 13.25 ms had a 98% negative predictive value. // Conclusions: This study demonstrates that remote wireless HRV monitoring identifies cirrhosis patients at high risk of developing ACLF and death, and suggests such monitoring might guide the need for early intervention in such patients. Clinical Trial number: NIHR clinical research network CPMS ID 4949

Massively parallel functional dissection of mammalian enhancers in vivo

The functional consequences of genetic variation in mammalian regulatory elements are poorly understood. We report the in vivo dissection of three mammalian liver enhancers at single nucleotide resolution via a massively parallelized reporter assay. For each enhancer, we synthesized a library of >100,000 mutant haplotypes with 2–3% divergence from wild-type. Each haplotype was linked to a unique sequence tag embedded within a transcriptional cassette. We introduced each enhancer library into mouse liver and measured the relative activities of individual haplotypes en masse by sequencing of the transcribed tags. Linear regression yielded highly reproducible estimates of the impact of every possible single nucleotide change on enhancer activity. The functional impact of most mutations was modest, with ~22% impacting activity by >1.2-fold, and only ~3% by >2-fold. These results suggest that mammalian enhancers are relatively robust to single nucleotide changes. Several, but not all positions with higher impact showed evidence for purifying selection, or co-localized with known liver-associated transcription factor binding sites, demonstrating the value of empirical high-resolution functional analysis