Time-Restricted Feeding Improves Circadian Dysfunction as well as Motor Symptoms in the Q175 Mouse Model of Huntington's Disease.

Huntington's disease (HD) patients suffer from a progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular, and motor dysfunction. Disturbances in sleep/wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and fatigue during the day. The heterozygous Q175 mouse model of HD has been shown to phenocopy many HD core symptoms including circadian dysfunctions. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early intervention that improve circadian rhythmicity can benefit HD and delay disease progression. We determined the effects of time-restricted feeding (TRF) on the Q175 mouse model. At six months of age, the animals were divided into two groups: ad libitum (ad lib) and TRF. The TRF-treated Q175 mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle of the time when mice are normally active. After three months of treatment (when mice reached the early disease stage), the TRF-treated Q175 mice showed improvements in their locomotor activity rhythm and sleep awakening time. Furthermore, we found improved heart rate variability (HRV), suggesting that their autonomic nervous system dysfunction was improved. Importantly, treated Q175 mice exhibited improved motor performance compared to untreated Q175 controls, and the motor improvements were correlated with improved circadian output. Finally, we found that the expression of several HD-relevant markers was restored to WT levels in the striatum of the treated mice using NanoString gene expression assays

Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease.

Cardiovascular dysautonomia as well as the deterioration of circadian rhythms are among the earliest detectable pathophysiological changes in individuals with Huntington's disease (HD). Preclinical research requires mouse models that recapitulate disease symptoms and the Q175 knock-in model offers a number of advantages but potential autonomic dysfunction has not been explored. In this study, we sought to test the dual hypotheses that cardiovascular dysautonomia can be detected early in disease progression in the Q175 model and that this dysfunction varies with the daily cycle. Using radiotelemetry implants, we observed a significant reduction in the diurnal and circadian activity rhythms in the Q175 mutants at the youngest ages. By middle age, the autonomically driven rhythms in core body temperature were highly compromised, and the Q175 mutants exhibited striking episodes of hypothermia that increased in frequency with mutant huntingtin gene dosage. In addition, Q175 mutants showed higher resting heart rate (HR) during sleep and greatly reduced correlation between activity and HR HR variability was reduced in the mutants in both time and frequency domains, providing more evidence of autonomic dysfunction. Measurement of the baroreceptor reflex revealed that the Q175 mutant could not appropriately increase HR in response to a pharmacologically induced decrease in blood pressure. Echocardiograms showed reduced ventricular mass and ejection fraction in mutant hearts. Finally, cardiac histopathology revealed localized points of fibrosis resembling those caused by myocardial infarction. Thus, the Q175 mouse model of HD exhibits cardiovascular dysautonomia similar to that seen in HD patients with prominent sympathetic dysfunction during the resting phase of the activity rhythm

Multi-ethnic genome-wide association study for atrial fibrillation

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.Peer reviewe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Circadian and ultradian rhythms in normal mice and in a mouse model of Huntington’s disease

Circadian rhythms in core body temperature (CBT) have been widely studied, but fewer studies have explored higher-frequency (ultradian) rhythms in detail. We analyzed CBT recordings from young and middle-aged wild-type mice as well as from the Q175 model of Huntington's disease (HD), at sufficient temporal resolution to address the question of ultradian rhythms. We used model selection methods to show that the overall circadian pattern was better fit by a square wave than a sine wave. Then, using Fourier analysis of the CBT rhythms, we identified the spectral signature of an 8-hour oscillation that occurs in the night but not the day, an observation that can be confirmed by direct inspection of the rhythms. This diurnal amplitude modulation of the 8-hour rhythm was lost with aging as well as in the HD model. Thus, the impact of aging and disease is seen here in the loss of the ability to separate rhythms into a daytime phase and a nighttime phase. These findings raise the possibility that ultradian rhythms in CBT may be a useful biomarker for the pathology within the central nervous system

Time-Restricted Feeding Improves Circadian Dysfunction as well as Motor Symptoms in the Q175 Mouse Model of Huntington's Disease.

Huntington's disease (HD) patients suffer from a progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular, and motor dysfunction. Disturbances in sleep/wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and fatigue during the day. The heterozygous Q175 mouse model of HD has been shown to phenocopy many HD core symptoms including circadian dysfunctions. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early intervention that improve circadian rhythmicity can benefit HD and delay disease progression. We determined the effects of time-restricted feeding (TRF) on the Q175 mouse model. At six months of age, the animals were divided into two groups: ad libitum (ad lib) and TRF. The TRF-treated Q175 mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle of the time when mice are normally active. After three months of treatment (when mice reached the early disease stage), the TRF-treated Q175 mice showed improvements in their locomotor activity rhythm and sleep awakening time. Furthermore, we found improved heart rate variability (HRV), suggesting that their autonomic nervous system dysfunction was improved. Importantly, treated Q175 mice exhibited improved motor performance compared to untreated Q175 controls, and the motor improvements were correlated with improved circadian output. Finally, we found that the expression of several HD-relevant markers was restored to WT levels in the striatum of the treated mice using NanoString gene expression assays

Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis.

Disturbances in sleep/wake cycle are a common complaint of individuals with Huntington's disease (HD) and are displayed by HD mouse models. The underlying mechanisms, including the possible role of the circadian timing system, have been the topic of a number of recent studies. The (z)Q175 mouse is a knock-in model in which the human exon 1 sequence of the huntingtin gene is inserted into the mouse DNA with approximately 190 CAG repeats. Among the numerous models available, the heterozygous Q175 offers strong construct validity with a single copy of the mutation, genetic precision of the insertion and control of mutation copy number. In this review, we will summarize the evidence that this model exhibits disrupted diurnal and circadian rhythms in locomotor activity. We found overwhelming evidence for autonomic dysfunction including blunted daily rhythms in heart rate and core body temperature (CBT), reduced heart rate variability, and almost a complete failure of the sympathetic arm of the autonomic nervous system to function during the baroreceptor reflex. Mechanistically, the Q175 mouse model exhibits deficits in the neural output of the central circadian clock, the suprachiasmatic nucleus along with an enhancement of at least one type of potassium current in these neurons. Finally, we report a novel network analysis examining the phase coherence between activity, CBT, and cardiovascular measures. Such analyses found that even young Q175 mutants (heterozygous or homozygous) show coherence degradation, and suggests that loss of phase coherence is a variable that should be considered as a possible biomarker for HD

Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease.

Cardiovascular dysautonomia as well as the deterioration of circadian rhythms are among the earliest detectable pathophysiological changes in individuals with Huntington's disease (HD). Preclinical research requires mouse models that recapitulate disease symptoms and the Q175 knock-in model offers a number of advantages but potential autonomic dysfunction has not been explored. In this study, we sought to test the dual hypotheses that cardiovascular dysautonomia can be detected early in disease progression in the Q175 model and that this dysfunction varies with the daily cycle. Using radiotelemetry implants, we observed a significant reduction in the diurnal and circadian activity rhythms in the Q175 mutants at the youngest ages. By middle age, the autonomically driven rhythms in core body temperature were highly compromised, and the Q175 mutants exhibited striking episodes of hypothermia that increased in frequency with mutant huntingtin gene dosage. In addition, Q175 mutants showed higher resting heart rate (HR) during sleep and greatly reduced correlation between activity and HR HR variability was reduced in the mutants in both time and frequency domains, providing more evidence of autonomic dysfunction. Measurement of the baroreceptor reflex revealed that the Q175 mutant could not appropriately increase HR in response to a pharmacologically induced decrease in blood pressure. Echocardiograms showed reduced ventricular mass and ejection fraction in mutant hearts. Finally, cardiac histopathology revealed localized points of fibrosis resembling those caused by myocardial infarction. Thus, the Q175 mouse model of HD exhibits cardiovascular dysautonomia similar to that seen in HD patients with prominent sympathetic dysfunction during the resting phase of the activity rhythm

Child mortality and fertility: public vs private education

Child mortality, Fertility, Human capital, I20, J13, O40,