Abstract Title

Brief Exposure to Intermittent Hypoxia Prolongs QTc in Human Subjects, which is Abrogated with AT1a Receptor Blockade.

Presenter Name

Noah P Jouett

RAD Assignment Number

414

Abstract

Purpose: Patients with Obstructive Sleep Apnea (OSA) frequently succumb to sudden cardiac death (SCD). Prolongation of the QTc, possibly via intermittent hypoxia (IH) mediated activation of angiotensin II type 1a receptors (ATR1a), predisposes towards SCD. Hence, the present study tested the hypothesis that (1) a brief exposure of IH lengthens QTc which (2) is abrogated with Losartan, an antagonist of ATR1a. Further, we evaluated how Losartan affects the relationship between direct measurements of muscle SNA (MSNA) and QTc via linear regression analyses during IH.

Methods: Seven healthy human subjects were recruited with normal 12-lead ECGs. Subjects ingested either placebo or 100 mg of Losartan 1 hour prior to experimentation, and then repeated the study on a separate day in a randomized, repeated measures design. 3-lead ECG and MSNA (peroneal microneurography) were recorded throughout the study. Subjects were exposed to 20 minutes of IH, which was composed of 20 cycles of the following: 2-3 breaths of 95-100% N2, 20-second end-expiratory apnea, and 40-second room-air recovery. QTc (determined by Bazett’s formula) averages were compared statistically using a repeated-measures ANOVA.

Results: Losartan did not alter baseline QTc (P = 0.17). IH + Placebo significantly prolonged QTc (baseline: 359.8 ± 4.8 ms vs. IH: 368.3 ± 4.8 ms, P < 0.001). Losartan abrogated the IH-mediated QTc prolongation (baseline: 364.5 ± 5.7 ms vs. IH: 367 ± 6.4 ms, P = 0.11). Furthermore, changes in MSNA explained only 6% of the variance in QTc during IH with Placebo, which increased to 22% with IH and Losartan (IH + Placebo: R2 = 0.06, IH + Losartan: R2: 0.22).

Conclusions: IH prolongs QTc, which is prevented with Losartan . Furthermore, IH alters the relationship of MSNA and QTc, in part through activation of ATR1a. Future studies should evaluate the possible cardioprotective benefits of ATR1a antagonists in OSA patients.

Research Area

Cardiovascular

Presentation Type

Poster

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Brief Exposure to Intermittent Hypoxia Prolongs QTc in Human Subjects, which is Abrogated with AT1a Receptor Blockade.

Purpose: Patients with Obstructive Sleep Apnea (OSA) frequently succumb to sudden cardiac death (SCD). Prolongation of the QTc, possibly via intermittent hypoxia (IH) mediated activation of angiotensin II type 1a receptors (ATR1a), predisposes towards SCD. Hence, the present study tested the hypothesis that (1) a brief exposure of IH lengthens QTc which (2) is abrogated with Losartan, an antagonist of ATR1a. Further, we evaluated how Losartan affects the relationship between direct measurements of muscle SNA (MSNA) and QTc via linear regression analyses during IH.

Methods: Seven healthy human subjects were recruited with normal 12-lead ECGs. Subjects ingested either placebo or 100 mg of Losartan 1 hour prior to experimentation, and then repeated the study on a separate day in a randomized, repeated measures design. 3-lead ECG and MSNA (peroneal microneurography) were recorded throughout the study. Subjects were exposed to 20 minutes of IH, which was composed of 20 cycles of the following: 2-3 breaths of 95-100% N2, 20-second end-expiratory apnea, and 40-second room-air recovery. QTc (determined by Bazett’s formula) averages were compared statistically using a repeated-measures ANOVA.

Results: Losartan did not alter baseline QTc (P = 0.17). IH + Placebo significantly prolonged QTc (baseline: 359.8 ± 4.8 ms vs. IH: 368.3 ± 4.8 ms, P < 0.001). Losartan abrogated the IH-mediated QTc prolongation (baseline: 364.5 ± 5.7 ms vs. IH: 367 ± 6.4 ms, P = 0.11). Furthermore, changes in MSNA explained only 6% of the variance in QTc during IH with Placebo, which increased to 22% with IH and Losartan (IH + Placebo: R2 = 0.06, IH + Losartan: R2: 0.22).

Conclusions: IH prolongs QTc, which is prevented with Losartan . Furthermore, IH alters the relationship of MSNA and QTc, in part through activation of ATR1a. Future studies should evaluate the possible cardioprotective benefits of ATR1a antagonists in OSA patients.