Obstructive sleep apnea, which involves chronic intermittent hypoxia (CIH), is a major risk factor for developing atrial fibrillation (AF). Whether or not CIH alone alters cardiac mechanisms to ...support AF is unknown. This study investigated the effects of CIH on atrial electrophysiology and arrhythmia vulnerability and evaluated the role of autonomics in CIH promotion of AF. Adult male Sprague-Dawley rats were exposed to 8 h/day of CIH or normoxia for 7 days. After exposure, rats were anesthetized for intracardiac electrophysiological experiments. Atrial effective refractory periods (AERPs) and AF inducibility were determined using programmed electrical stimulation and burst pacing in the absence and presence of autonomic receptor agonists and antagonists. Western blot analysis measured atrial protein expression of muscarinic M2, M3, and β
-adrenergic receptors. Compared with normoxia-exposed control rats, CIH-exposed rats had enhanced AF vulnerability using both programmed electrical stimulation and burst pacing, accompanied by greater AERP responses to carbachol and propranolol, lesser responses to isoproterenol, and higher atrial M2 receptor protein levels. Enhanced atrial vulnerability was accentuated by carbachol and abolished by atropine, indicating that the AF-promoting effects of CIH depended principally on parasympathetic activation. Enhancement of atrial vulnerability and AERP shortening with cholinergic agonists in CIH-exposed rats is consistent with sensitivity to parasympathetic activation. Higher responses to adrenergic receptor blockade in CIH-exposed rats is consistent with sympathetic potentiation. These findings implicate CIH as an important mediator of enhanced AF susceptibility in obstructive sleep apnea and provide novel insights into the underlying mechanisms. NEW & NOTEWORTHY Our study demonstrates, for the first time, that chronic intermittent hypoxia alone enhances vulnerability to atrial arrhythmia induction, which depends principally on parasympathetic activation. Enhanced atrial vulnerability was accompanied by heightened electrophysiological responses of the atrial myocardium to carbachol and isoproterenol, dampened responses to propranolol, and increased atrial M2 receptor protein levels.
Cannabis has been widely used as a medicinal agent in Eastern medicine with earliest evidence in ancient Chinese practice dating back to 2700 BC. Over time, the use of medical cannabis has been ...increasingly adopted by Western medicine and is thus a rapidly emerging field that all pain physicians need to be aware of. Several randomized controlled trials have shown a significant and dose-dependent relationship between neuropathic pain relief and tetrahydrocannabinol - the principal psychoactive component of cannabis. Despite this, barriers exist to use from both the patient perspective (cost, addiction, social stigma, lack of understanding regarding safe administration) and the physician perspective (credibility, criminality, clinical evidence, patient addiction, and policy from the governing medical colleges). This review addresses these barriers and draws attention to key concerns in the Canadian medical system, providing updated treatment approaches to help clinicians work with their patients in achieving adequate pain control, reduced narcotic medication use, and enhanced quality of life. This review also includes case studies demonstrating the use of medical marijuana by patients with neuropathic low-back pain, neuropathic pain in fibromyalgia, and neuropathic pain in multiple sclerosis. While significant preclinical data have demonstrated the potential therapeutic benefits of cannabis for treating pain in osteoarthritis, rheumatoid arthritis, fibromyalgia, and cancer, further studies are needed with randomized controlled trials and larger study populations to identify the specific strains and concentrations that will work best with selected cohorts.
Abstract
Aims
Rare variants in the KCNQ1 gene are found in the healthy population to a much greater extent than the prevalence of Long QT Syndrome type 1 (LQTS1). This observation creates challenges ...in the interpretation of KCNQ1 rare variants that may be identified as secondary findings in whole exome sequencing.
This study sought to identify missense variants within sub-domains of the KCNQ1-encoded Kv7.1 potassium channel that would be highly predictive of disease in the context of secondary findings.
Methods and results
We established a set of KCNQ1 variants reported in over 3700 patients with diagnosed or suspected LQTS sent for clinical genetic testing and compared the domain-specific location of identified variants to those observed in an unselected population of 140 000 individuals. We identified three regions that showed a significant enrichment of KCNQ1 variants associated with LQTS at an odds ratio (OR) >2: the pore region, and the adjacent 5th (S5) and 6th (S6) transmembrane (TM) regions. An additional segment within the carboxyl terminus of Kv7.1, conserved region 2 (CR2), also showed an increased OR of disease association. Furthermore, the TM spanning S5–Pore–S6 region correlated with a significant increase in cardiac events.
Conclusion
Rare missense variants with a clear phenotype of LQTS have a high likelihood to be present within the pore and adjacent TM segments (S5–Pore–S6) and a greater tendency to be present within CR2. This data will enhance interpretation of secondary findings within the KCNQ1 gene. Further, our data support a more severe phenotype in LQTS patients with variants within the S5–Pore–S6 region.
Structured Graphical Abstract
Structured Graphical Abstract
ABSTRACT
Ligase IV syndrome is a rare differential diagnosis for Nijmegen breakage syndrome owing to a shared predisposition to lympho‐reticular malignancies, significant microcephaly, and radiation ...hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here, we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC −10.1 s.d., height −5.1 s.d.). Subsequently, most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognized immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype–phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency, and sometimes malignancy are long term sequelae of this disorder.
Ligase IV syndrome, a rare disorder of DNA damage repair, is associated with severe immunodeficiency, malignancy predisposition, and microcephaly. Here, we report that mutations in LIG4 also occur in patients presenting with extreme growth failure, extending the phenotypic spectrum of Ligase IV deficiency. A correlation between degree of protein truncation and disease severity is observed, with a recurrent mutation presenting in conjunction with a more severely truncating mutation conferring profound growth impairment with progressive bone marrow failure and immunodeficiency.
Abstract only Introduction Obstructive sleep apnea (OSA) is a risk factor for developing atrial fibrillation (AF), but the mechanisms underlying AF are unknown. OSA is characterized by airway ...obstruction and intermittent hypoxia (IH), which has been implicated in the induction of cardiovascular dysfunction. However, the role of IH in predisposing the atria to AF is not understood. Hypothesis This study tested the hypothesis that chronic repetitive IH enhances autonomic responses, and predisposes the atria to AF. Materials and Methods Adult, male Sprague‐Dawley rats were exposed to normoxia or repeated cycles of 120 s 21% O 2 alternated with 80 s 6.5–8% O 2 for 8h/day for 7 days. Rats exposed to 7 days of IH or normoxia had in vivo intracardiac electrophysiology studies to evaluate electrophysiological characteristics and susceptibility to electrical inducibility of AF. Atrial effective refractory periods were determined using programmed electrical stimulation (PES) at two atrial locations. Susceptibility to electrically induced AF was determined using PES with 8 stimuli at basic drive cycle lengths of 150 or 100 ms followed by a sequentially premature single extrastimumus and burst pacing using up to 30, 1 sec burst at 50 Hz. Results Rats following 7‐days of IH exposure were more susceptible to electrical induction of atrial arrhythmia than normoxic controls (50% vs 0%, respectively, P < 0.05). This was accompanied by an increase in inducibility in the presence of carbachol which was blocked by atropine and darifenacin. The response to isoproterenol were enhanced in the normoxic but not in the IH rats, and the effects of propranolol were less pronounced in the IH rats. Conclusions We have demonstrated for the first time that repeated exposure to IH in rats produced enhanced sensitivity to atrial arrhythmias. These novel findings implicating IH as a critical promoter of AF in an OSA model. Accentuation with cholinergic agonists and blockade with nonspecific and M3 specific antagonists is consistent with sensitivity to parasympathetic activation which is known to predispose the atria to AF. The diminished response to sympathetic agents suggests a potential desensitization to adrenergic activation in the IH rats. These novel findings provide an indication of the importance of IH in OSA and susceptibility to atrial arrhythmia and potential for novel therapies in OSA. Support or Funding Information Supported in part by the Heart and Stroke Foundation of Ontario
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