Social Determinants of Genetics Referral and Completion Rates Among Child Neurology Patients.

Objective: To investigate clinical, social, and systems-level determinants predictive of genetics clinic referral and completion of genetics clinic visits among child neurology patients. Methods: Electronic health record data were extracted from patients 0-18 years old who were evaluated in child neurology clinics at a single tertiary care institution between July 2018 to January 2020. Variables aligned with the Health Equity Implementation Framework. Referral and referral completion rates to genetics and cardiology clinics were compared among Black vs White patients using bivariate analysis. Demographic variables associated with genetics clinic referral and visit completion were identified using logistic regressions. Results: In a cohort of 11,371 child neurology patients, 304 genetics clinic referrals and 82 cardiology clinic referrals were placed. In multivariate analysis of patients with Black or White ethnoracial identity (n=10,601), genetics clinic referral rates did not differ by race, but were significantly associated with younger age, rural address, neurodevelopmental disorder diagnosis, number of neurology clinic visits, and provider type. The only predictors of genetics clinic visit completion number of neurology clinic visits and race/ethnicity, with White patients being twice as likely as Black patients to complete the visit. Cardiology clinic referrals and visit completion did not differ by race/ethnicity. Interpretation: Although race/ethnicity was not associated with differences in genetics clinic referral rates, White patients were twice as likely as Black patients to complete a genetics clinic visit after referral. Further work is needed to determine whether this is due to systemic/structural racism, differences in attitudes toward genetic testing, or other factors.

An open sarcolemmal adenosine triphosphate-sensitive potassium channel is necessary for detrimental myocyte swelling secondary to stress.

BACKGROUND: Stress (exposure to hyperkalemic cardioplegia, metabolic inhibition, or osmotic) results in significant myocyte swelling and reduced contractility. In contrast to wild-type mice, these detrimental consequences are not observed in mice lacking the Kir6.2 subunit of the sarcolemmal ATP-sensitive potassium (sK(ATP)) channel after exposure to hyperkalemic cardioplegia. The hypothesis for this study was that an open sK(ATP) channel (Kir6.2 and SUR2A subunits) is necessary for detrimental myocyte swelling to occur in response to stress. METHODS AND RESULTS: To investigate the role of the sK(ATP) channel in stress-induced myocyte swelling, high-dose pharmacological sK(ATP) channel blockade and genetic deletion (knockout of Kir6.2 subunit) were used. Myocytes were exposed sequentially to Tyrode control (20 minutes), test (stress) solution (20 minutes), and Tyrode control (20 minutes). To evaluate pharmacological channel blockade, myocytes were exposed to hyperkalemic cardioplegia (stress) with and without a K(ATP) channel blocker. To evaluate the effects of genetic deletion, wild-type and sK(ATP) knockout [Kir6.2(-/-)] myocytes were exposed to metabolic inhibition (stress). Myocyte volume was recorded using image-grabbing software. Detrimental myocyte swelling was prevented by high-dose sK(ATP) channel blockade (glibenclamide or HMR 1098) but not mitochondrial K(ATP) channel blockade (5-hydroxydecanoate) during exposure to hyperkalemic cardioplegia. Genetic deletion of the sK(ATP) channel prevented significant myocyte swelling in response to metabolic inhibition. CONCLUSIONS: K(ATP) channel openers prevent detrimental myocyte swelling and reduce contractility in response to stress through an unknown mechanism. Paradoxically, the present data support a role for sK(ATP) channel activation in myocyte volume derangement in response to stress.

Myocyte volume and function in response to osmotic stress: observations in the presence of an adenosine triphosphate-sensitive potassium channel opener.

BACKGROUND: Hypothermic hyperkalemic cardioplegia results in significant myocyte swelling and impaired contractility. These detrimental effects may be eliminated by the addition of an adenosine triphosphate-sensitive potassium (KATP) channel opener. This study evaluated the hypothesis that a KATP channel opener (diazoxide) would benefit volume homeostasis by limiting volume and subsequent contractility changes during osmotic stress. METHODS AND RESULTS: Isolated rabbit ventricular myocyte volume and contractility were evaluated using video microscopy and field stimulation after exposure to osmotic stress at 37 degrees C. Myocytes were exposed to Tyrode's physiological solution for 20 minutes and test solution for 20 minutes, and then reexposed to Tyrode's for 20 minutes. Test solutions included control Tyrode's (1T) and osmotically altered Tyrode's (2.6T, 0.9T, and 0.6T) solutions with or without the KATP channel opener diazoxide. Severe osmotic stress (2.6T and 0.6T) resulted in significant cell shrinkage and swelling, respectively. This was unchanged by the addition of diazoxide. Mild hyposmotic stress (0.9T) resulted in significant cell swelling that was eliminated by the addition of diazoxide. Cell swelling was associated with reduced contractility. CONCLUSIONS: Cell swelling, but not shrinkage, was detrimental to myocyte contractility. Diazoxide eliminated volume change due to mild hyposmotic stress, similar to that previously noted with hyperkalemic cardioplegia, but did not alter volume change secondary to severe osmotic stress.

Diazoxide maintains human myocyte volume homeostasis during stress.

BACKGROUND: Exposure to hypothermic hyperkalemic cardioplegia, hyposmotic stress, or metabolic inhibition results in significant animal myocyte swelling (6% to10%) and subsequent reduced contractility (10% to 20%). Both are eliminated by the adenosine triphosphate-sensitive potassium channel opener diazoxide (DZX). The relationship between swelling and reduced contractility suggests that the structural change may represent one mechanism of postoperative myocardial stunning. This study evaluated human myocyte volume during stress to investigate if similar phenomena exist in human myocytes. METHODS AND RESULTS: Human atrial myocytes isolated from tissue obtained during cardiac surgery were perfused with Tyrode's physiological solution (20 minutes, 37°C), test solution (20 minutes), and Tyrode's (37°C, 20 minutes). Test solutions (n=6 to 12 myocytes each) included Tyrode's (37°C or 9°C), Tyrode's+DZX (9°C), hyperkalemic cardioplegia (9°C)±DZX, cardioplegia+DZX+HMR 1098 (sarcolemmal adenosine triphosphate-sensitive potassium channel inhibitor, 9°C), cardioplegia+DZX+5-hydroxydeconoate (mitochondrial adenosine triphosphate-sensitive potassium channel inhibitor, 9°C), mild hyposmotic solution±DZX, metabolic inhibition±DZX, and metabolic inhibition+DZX+5-hydroxydeconoate. Myocyte volume was recorded every 5 minutes. Exposure to hypothermic hyperkalemic cardioplegia, hyposmotic stress, or metabolic inhibition resulted in significant human myocyte swelling (8%, 7%, and 6%, respectively; all P<0.05 vs control). In all groups, the swelling was eliminated or lessened by DZX. The addition of channel inhibitors did not significantly alter results. CONCLUSIONS: DZX maintains human myocyte volume homeostasis during stress via an unknown mechanism. DZX may prove to be clinically useful following the elucidation of its specific mechanism of action. (J Am Heart Assoc. 2012;1:jah3-e000778 doi: 10.1161/JAHA.112.000778.).

Diazoxide maintenance of myocyte volume and contractility during stress: evidence for a non-sarcolemmal K(ATP) channel location.

OBJECTIVE: Animal and human myocytes demonstrate significant swelling and reduced contractility during exposure to stress (metabolic inhibition, hyposmotic stress, or hyperkalemic cardioplegia), and these detrimental consequences may be inhibited by the addition of diazoxide (adenosine triphosphate-sensitive potassium channel opener) via an unknown mechanism. Both SUR1 and SUR2A subunits have been localized to the heart, and mouse sarcolemmal adenosine triphosphate-sensitive potassium channels are composed of SUR2A/Kir6.2 subunits in the ventricle and SUR1/Kir6.2 subunits in the atria. This study was performed to localize the mechanism of diazoxide by direct probing of sarcolemmal adenosine triphosphate-sensitive potassium channel current and by genetic deletion of channel subunits. METHODS: Sarcolemmal adenosine triphosphate-sensitive potassium channel current was recorded in isolated wild-type ventricular mouse myocytes during exposure to Tyrode's solution, Tyrode's + 100 µmol/L diazoxide, hyperkalemic cardioplegia, cardioplegia + diazoxide, cardioplegia + 100 µmol/L pinacidil, or metabolic inhibition using whole-cell voltage clamp (N = 7-12 cells per group). Ventricular myocyte volume was measured from SUR1(-/-) and wild-type mice during exposure to control solution, hyperkalemic cardioplegia, or cardioplegia + 100 µmol/L diazoxide (N = 7-10 cells per group). RESULTS: Diazoxide did not increase sarcolemmal adenosine triphosphate-sensitive potassium current in wild-type myocytes, although they demonstrated significant swelling during exposure to cardioplegia that was prevented by diazoxide. SUR1(-/-) myocytes also demonstrated significant swelling during exposure to cardioplegia, but this was not altered by diazoxide. CONCLUSIONS: Diazoxide does not open the ventricular sarcolemmal adenosine triphosphate-sensitive potassium channel but provides volume homeostasis via an SUR1-dependent pathway in mouse ventricular myocytes, supporting a mechanism of action distinct from sarcolemmal adenosine triphosphate-sensitive potassium channel activation.