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BACKGROUND: Autism spectrum disorder (ASD) and epilepsy are highly comorbid, suggesting potential overlap in genetic etiology, pathophysiology, and neurodevelopmental abnormalities; however, the nature of this relationship remains unclear. This work investigated how two ion channel mutations, one associated with autism (Scn2a-null) and one with epilepsy (Kcna1-null), interact to modify genotype-phenotype relationships in the context of autism. Previous studies have shown that Scn2a+/- ameliorates epilepsy in Kcna1-/- mice, improving survival, seizure characteristics, and brain-heart dynamics. Here, we tested the converse, whether Kcna1 deletion modifies ASD-like repetitive and social behaviors in Scn2a+/- mice. METHODS: Mice were bred with various combinations of Kcna1 and Scn2a knockout alleles. Animals were assessed for repetitive behaviors using marble burying, grooming, and nestlet shredding tests and for social behaviors using sociability and social novelty preference tests. RESULTS: Behavioral testing revealed drastic reductions in all repetitive behaviors in epileptic Kcna1-/- mice, but relatively normal social interactions. In contrast, mice with partial Kcna1 deletion (Kcna1+/- ) exhibited increased self-grooming and decreased sociability suggestive of ASD-like features similar to those observed in Scn2a+/- mice. In double-mutant Scn2a+/- ; Kcna1+/- mice, the two mutations interacted to partially normalize ASD-like behaviors associated with each mutation independently. CONCLUSIONS: Taken together, these findings suggest that Kv1.1 subunits are important in pathways and neural networks underlying ASD and that Kcna1 may be a therapeutic target for treatment of Scn2a-associated ASD.

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Goal: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality and its pathophysiological mechanisms remain unknown. We set to record and analyze for the first time concurrent electroencephalographic (EEG), electrocardiographic (ECG), and unrestrained whole-body plethysmographic (Pleth) signals from control (WT - wild type) and SUDEP-prone mice (KO- knockout Kcna1 animal model). Employing multivariate autoregressive models (MVAR) we measured all tri-organ effective directional interactions by the generalized partial directed coherence (GPDC) in the frequency domain over time (hours). When compared to the control (WT) animals, the SUDEP-prone (KO) animals exhibited (p < 0.001) reduced afferent and efferent interactions between the heart and the brain over the full frequency spectrum (0-200Hz), enhanced efferent interactions from the brain to the lungs and from the heart to the lungs at high (>90 Hz) frequencies (especially during periods with seizure activity), and decreased feedback from the lungs to the brain at low (<40 Hz) frequencies. These results show that impairment in the afferent and efferent pathways in the holistic neuro-cardio-respiratory network could lead to SUDEP, and effective connectivity measures and their dynamics could serve as novel biomarkers of susceptibility to SUDEP and seizures respectively.

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BACKGROUND & OBJECTIVES: Although insulin resistance (IR) is a known complication in obesity, the physiological mechanisms linking IR with cardiometabolic risks in obesity have not been well studied. This study was conducted to assess the difference in cardiovascular (CV) risk profile in IR and non-IR (NIR) conditions, and contribution of IR to cardiometabolic risks in pre-obese and obese individuals. METHODS: Basal CV, blood pressure variability, autonomic function test and cardiometabolic parameters were recorded in pre-obese (n=86) and obese (n=77) individuals during 2012 and 2015. The association of altered cardiometabolic parameters with homeostatic model for IR (HOMA-IR) in pre-obese and obese groups and with baroreceptor sensitivity (BRS) in IR and NIR groups was calculated by appropriate statistical analysis. RESULTS: Decreased BRS, a known CV risk and cardiometabolic parameters were significant in IR (pre-obese and obese) group compared to the NIR group. Sympathovagal imbalance in the form of increased sympathetic and decreased parasympathetic activities was observed in individuals with IR. There was no significant difference in the level of independent contribution of HOMA-IR to cardiometabolic parameters in pre-obese and obese groups. Adiponectin and inflammatory markers had an independent contribution to BRS in IR group. INTERPRETATION & CONCLUSIONS: Findings of the present study demonstrated that the intensity of cardiometabolic derangements and CV risk were comparable between IR, pre-obese and obese individuals. Pro-inflammatory state, dyslipidaemia and hypoadiponectinaemia might contribute to CV risk in these individuals with IR. IR could possibly be the link between altered metabolic profile and increased CV risks in these individuals independent of the adiposity status.

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Though endothelial nitric oxide synthase (eNOS) gene polymorphism is documented in the causation of hypertension, its role in prehypertension has not been investigated. The present study was conducted in 172 subjects divided into prehypertensives (n = 57) and normotensives (n = 115). Cardiovascular (CV) parameters including baroreflex sensitivity (BRS) by continuous BP variability assessment and sympathovagal imbalance (SVI) by heart rate variability analysis were recorded. Biochemical parameters for insulin resistance (homeostatic model for assessment of insulin resistance), oxidative stress, lipid risk factors, renin, and inflammatory parameters were measured. Genotyping for eNOS polymorphisms rs1799983 (298G>T) and rs2070744 (-786T>C) was performed by polymerase chain reaction-restriction fragment length polymorphism method. Multiple regression analysis was done to assess the association between SVI and metabolic markers, and multivariate logistic regression was done to determine the prediction of prehypertension status by genotype, BRS, and ratio of low-frequency to high-frequency in these subjects. The BP variability, heart rate variability, and biochemical parameters were significantly altered in prehypertensives. The eNOS polymorphisms were found to be associated with prehypertension. BRS, the marker of SVI, was significantly associated with BP, homeostatic model for assessment of insulin resistance, and tumor necrosis factor alpha in 298GG genotype of prehypertensive population. The eNOS gene polymorphisms appear to be associated with prehypertension. 298G>T and -786T>C contribute to SVI in young prehypertensives attributed by insulin resistance and inflammation. The CV risks were associated with prehypertension status in prehypertensives expressing both 298GG and -786TT genotypes. Association of CV risks with SVI appears to be stronger in prehypertensives expressing GG genotype.

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OBJECTIVE: Though decreased baroreflex sensitivity (BRS), the predictor of cardiac morbidities and mortality has been reported in obesity, the mechanisms and metabolic biomarkers influencing BRS have not been studied. We aimed to assess the difference in cardiovascular (CV) risk profile in pre-obesity and obesity, and the contribution of body composition and cardiometabolic factors to CV risks in these two conditions. METHODS: Obesity indices, body composition, blood pressure variability and autonomic function test parameters were recorded in 223 subjects divided into controls (n=72), pre-obese (n=77) and obese (n=74) groups. Insulin resistance (HOMA-IR), atherogenic index (AI), leptin, adiponectin, inflammatory and oxidative stress parameters were measured. Association and independent contribution of altered cardiometabolic parameters with BRS were performed by Pearson's correlation and multiple regression analysis, respectively. RESULTS: BRS was significantly decreased in pre-obese and obese group compared to controls. Sympathovagal imbalance (SVI) in the form of increased sympathetic and decreased parasympathetic cardiac drives was observed in pre-obesity and obesity. There was significant difference in general markers of obesity (body mass index, and waist-to-hip ratio), between pre-obese and obese group, however no such difference was observed in body composition and cardiometabolic parameters between the two groups. AI, high sensitive C-reactive protein (hs-CRP) and ratio of basal metabolism to body fat (BM/BF) in pre-obese group, and AI, HOMA-IR, leptin, adiponectin, ratio of basal metabolism to body weight (BM/BW), BM/BF, inflammatory and oxidative stress markers in obese group had independent contribution to BRS. Among these metabolic biomarkers, BRS had maximum association with leptin (ß=0.532, p=0.000) in the obese group and hs-CRP (ß=0.445, p=0.022) in the pre-obese group. CONCLUSIONS: The present study demonstrates decreased BRS, an important marker of increased CV risk in pre-obesity and obesity. The intensity of cardiometabolic derangements and CV risk was comparable between pre-obese and obese subjects. BM/BF ratio appears to be a better marker of metabolic activity in pre-obesity and obesity. SVI and increased basal metabolism appear to be the physiological link between metabolic derangements and CV risks in both pre-obesity and obesity.

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Salt preference has been reported to cause sympathovagal imbalance (SVI) and prehypertension. We investigated the role of inflammation, insulin resistance (IR), hyperlipidemia, and oxidative stress (OS) in genesis of SVI and cardiovascular (CV) risks in salt-preferring prehypertensives. The subjects were divided into no-salt-preferring (NSP, n = 87) and salt-preferring (SP, n = 89) group based on their preference for salted food. Body mass index (BMI), blood pressure (BP) variability parameters including baroreflex sensitivity (BRS), heart rate variability (HRV) indices, autonomic function tests, IR, lipid risk factors, inflammatory and OS markers, and renin were measured in both the groups. Based on the contribution of various cardiometabolic risks to low-frequency-high-frequency (LF-HF) ratio of HRV, the marker of SVI was assessed by multiple-regression analysis. Prediction of prehypertension status by the LF-HF ratio was assessed by bivariate logistic regression. BMI, heart rate, BP parameters, cardiac output, total peripheral resistance, LF-HF ratio, IR, atherogenic index, inflammatory, and OS markers were significantly increased, and BRS was significantly decreased in the SP group compared with the NSP group. There was an independent association of IR, atherogenic index, markers of inflammation and OS, and BRS with the LF-HF ratio in SP subjects, and the LF-HF ratio had significant prediction of prehypertension status in these subjects. It was concluded that IR, low-grade inflammation, atherogenic lipid profile, and OS contribute to SVI in SP subjects. Decreased BRS (the marker of CV risk) is linked to SVI, and SVI predicts prehypertension status in SP subjects.

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