Heart rate phenotypes and clinical correlates in a large cohort of adults without sleep apnea

Figures & data

Figure 1 Examples of HR patterns from clinical PSGs.

Notes: (A) A 29-year-old male with fatigue, BMI 26 kg/m², with mildly increased HR trend in NREM sleep (all supine, absence of OSA, or PLMS). The top row shows HR values (bpm). The next row indicates scattered PLM events (limb movement). The third row indicates scattered AHI events. The bottom row shows the sleep–wake stages. In this and subsequent panels, the time scale is given as vertical dotted lines showing 1 hour intervals. In all panels, the recording time began between 10 and 10.30 pm. (B) A 51-year-old female with RLS and PLMS showing marked increase in NREM HR (all lateral position, BMI 25 kg/m², and absence of OSA). The top row shows HR values (bpm), the next row indicates PLMS events (limb movement), and the bottom row is sleep–wake stages. (C) An 80-year-old female with severe OSA (AHI 32), sleeping supine (BMI 30 kg/m²), with reactive HR increases associated with REM desaturating events. The top row is the pulse oximetry data (SpO₂), the next row is the HR, the third row is the SDB events contributing to the AHI, and the bottom row shows the sleep–wake stages.
Abbreviations: AHI, apnea–hypopnea index; BMI, body mass index; HR, heart rate; NREM, nonrapid eye movement; OSA, obstructive sleep apnea; PLM, periodic limb movements; PLMS, periodic limb movements in sleep; PSG, polysomnography; REM, rapid eye movement; RLS, restless legs syndrome; SDB, sleep-disordered breathing.

Table 1 Characteristics of the full cohort and clinically defined subsets

Metric	All	PLMI ≥15	ESS ≥11	MP ≥60 minutes
n	1047	339	285	283
Age (years)	43 (32–54)	49 (35–61)	41 (28–51)	40 (30–53)
Sex (% male)	39.5	45.4	33.3	32.5
BMI (kg/m^2)	27.3 (24.1–32.2)	27.2 (24.0–32.2)	26.8 (23.7–31.7)	27.2 (24.0–32.3)
ESS	7 (4–12)	7 (3–11)	13 (12–16)	6 (3–11)
TST (minutes)	384 (339–423)	368 (311–409)	400 (366–429)	395 (352–430)
N1%	10.6 (6.6–16.3)	14.6 (9.2–21.2)	9.7 (5.5–15.0)	10.9 (6.7–16.3)
N2%	53.6 (46.6–60.8)	53.6 (46.0–61.4)	53.7 (46.8–60.7)	52.9 (45.2–60.3)
N3%	17.4 (10.7–23.3)	14.4 (7.6–21.7)	17.7 (10.9–22.7)	18.8 (11.0–24.0)
REM%	16.0 (11.0–21.3)	14.7 (8.4–19.5)	16.7 (12.2–21.7)	16.0 (11.1–21.3)
Efficiency (%)	85 (76–91)	80 (69–88)	88 (81–93)	86 (78–91)
SL (minutes)	6.0 (2.0–14.0)	6.5 (2.5–16.5)	5.5 (2.0–12.8)	6.5 (2.5–13.0)
PLMI (1/hour)	7.4 (2.4–20.8)	31.6 (21.3–56.4)	6.8 (2.0–15.4)	6.7 (2.4–17.4)
HR–wake	62.3 (54.5–70.6)	61.5 (54.9–70.5)	62.6 (54.8–72.1)	63.9 (55.6–71.2)
HR–N1	63.7 (57.2–71.4)	63.4 (56.8–71.1)	65.5 (59.1–72.5)	64.8 (58.8–72.2)
HR–N2	62.9 (56.0–69.3)	62.5 (55.6–68.7)	63.5 (56.6–70.6)	63.5 (56.4–69.2)
HR–N3	64.2 (57.2–71.4)	63.5 (55.8–70.6)	64.8 (58.3–72.3)	64.8 (58.4–71.5)
HR–REM	64.6 (57.8–71.4)	63.2 (56.5–70.2)	65.5 (59.1–71.7)	65.6 (58.4–71.8)
Depression (%)	36.0	37.5	42.5	37.1
Anxiety (%)	41.5	41.3	44.2	43.8
Hypertension (%)	19.5	22.7	19.0	17.1
COPD (%)	1.5	1.8	1.8	1.4
CAD (%)	1.8	3.0	1.8	1.1
CHF (%)	1.5	1.5	1.8	1.1
DM (%)	6.1	6.8	6.0	6.7
Stroke (%)	2.1	4.4	2.5	1.4

Note: Data are either median (IQR) or percentage as noted.

Abbreviations: BMI, body mass index; CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; ESS, Epworth Sleepiness Scale; HR, heart rate; HRV, HR variability; IQR, interquartile range; MP, misperception; PLMI, periodic limb movement index; REM, rapid eye movement; SL, sleep latency; TST, total sleep time.

Figure 2 HR analysis across sleep–wake stages.

Notes: (A) HR values calculated from stable bouts (>5 minutes) of each sleep–wake stage. There were no differences between any of the stages. The waking HR values refer to any time spent awake while in bed for the PSG recording. (B) Histogram showing the proportion (%) of the cohort with lower HR value during N2 and N3, compared to wake of at least 0, 5, or 10% dipping. (C) Distribution of HR slope calculated for stable bouts of each sleep–wake stage across the cohort. The X-axis is the slope of a linear fit to each stable bout (in units of bpm). The zero-crossing value is the proportion of stable bouts that had a positive slope, and the inset is a zoom to show that the highest value was for wake and N1; by contrast, N3 had the greatest proportion of bouts showing a positive slope (lowest zero-crossing value on the Y-axis).
Abbreviations: HR, heart rate; PSG, polysomnography; REM, rapid eye movement.

Table 2 HRV correlations with selected clinical features

Metric	ESS	Quality	TST MP	PLMI
N1 LF	0.07	−0.03	0.14**	0.07
N1 HF	0.06	−0.05	−0.01	−0.04
N1 HF%	0.01	−0.03	−0.13**	−0.13**
N1 ratio	−0.01	0.06	0.14**	0.16**
N2 LF	−0.02	−0.04	0.01	0.06
N2 HF	−0.01	0.02	−0.02	−0.03
N2 HF%	0.00	0.07	−0.03	−0.10*
N2 ratio	−0.01	−0.05	0.03	0.11**
N3 LF	0.01	−0.04	0.02	−0.03
N3 HF	0.05	0.00	0.04	−0.13**
N3 HF%	0.04	0.04	0.02	−0.12**
N3 ratio	−0.03	−0.03	−0.02	0.14***
REM LF	0.02	0.02	0.00	−0.05
REM HF	0.04	0.07	−0.01	−0.01
REM HF%	0.05	0.08	−0.03	0.00
REM ratio	−0.06	−0.05	0.03	0.02
W LF	0.05	−0.03	0.06	0.06
W HF	0.06	0.02	0.04	0.01
W HF%	0.05	0.02	−0.01	−0.05
W ratio	−0.05	0.01	0.01	0.06

Notes: R-values are bold if >0.10 (Spearman correlation coefficient).

* P<0.05,

** P<0.005, and

*** P<0.0005.

Abbreviations: ESS, Epworth Sleepiness Scale; HF, high frequency; HRV, heart rate variability; LF, low frequency; MP, misperception; PLMI, periodic limb movement index; REM, rapid eye movement; TST, total sleep time; W, wake.

Figure 3 Clinical, PSG, and cardiac correlates of PLMS.

Notes: (A) Box and whiskers plot showing the distribution of age (years) for three prespecified categories of PLMI values. Brackets indicate significant differences between groups (Kruskal–Wallis with Dunn’s correction, P<0.0001). (B) Box and whiskers plot showing the distribution of N1 (%) for three prespecified categories of PLMI values. Brackets indicate significant differences between groups (Kruskal–Wallis with Dunn’s correction, P<0.0001). (C) Correlation coefficients reaching the predefined minimum value of |>0.1|, with the PLMI value across the cohort. P-values were <1×10⁻⁸ for N1%, age, N3%, REM%, TST, and efficiency. The remaining significant p-values were between 0.01 and 0.0001.
Abbreviations: HF, high frequency; HR, heart rate; HTN, hypertension; LF, low frequency; MP, misperception; PLM, periodic limb movements; PLMS, periodic limb movements in sleep; PLMI, periodic limb movement index; PSG, polysomnography; REM, rapid eye movement; TST, total sleep time; WHR, wake heart rate.

Figure 4 Clinical, PSG, and cardiac correlates of sleep quality and of misperception. Notes: (A) Box and whiskers plot showing the distribution of sleep efficiency (%) for prespecified categories of sleep quality. Bracket indicates significance (Mann–Whitney, P<0.003). (B) Box and whiskers plot showing the distribution of misperception of TST (subjective minus objective TST, in minutes) for prespecified categories of sleep quality. Bracket indicates significance (Mann–Whitney, P<0.0001). (C) Correlation coefficients reaching the predefined minimum value of |>0.1|, with the sleep quality value across the cohort. The P-values are all <0.005. (D) Correlation coefficients reaching the predefined minimum value of |>0.1|, with the TST misperception value across the cohort. The P-values are all <0.005.

Abbreviations: HF, high frequency; HR, heart rate; LF, low frequency; MP, misperception; oTST, objective TST; PSG, polysomnography; Qual, quality; sTST, subjective TST; TST, total sleep time; z-drug, zolpidem, zaleplon, eszopiclone.

Figure 5 Insomnia symptoms and objective TST.

Notes: The four possible combinations of binary total sleep time (TST; long [L] or short [S]) and insomnia symptom status (+ or −) are shown for age (A), N1 % (B), REM % (C), efficiency (D), PLMI (E), wake HR (F), N1 HR (G), N2 HR (H), N3 HR (I), and REM HR (J). In each panel, the box and whisker plots (5%–95%, with outliers shown as dots to illustrate variability) are given for four sub-cohorts based on objective TST value from the PSG (5.5 hours cutoff, for L or S values, and insomnia symptom level (high as + sign, low as - sign). These categories are given via X-axis labels, as well as the fill of the box plots: gray indicates insomnia symptom +, and speckled indicates <5.5 hours TST. Kruskal–Wallis testing results are shown with Dunn’s post hoc comparison of all possible group-wise pairs in each panel, where brackets indicate significant differences. The P-values were <0.0001 for all panels except wake and N1% (P<0.005).
Abbreviations: HR, heart rate; Ins, insomnia; L, long; PLMI, periodic limb movements index; PSG, polysomnography; REM, rapid eye movement; S, short; TST, total sleep time

Table 3 Objective short TST with insomnia symptoms

Metric	>5.5 hours TST	<5.5 hours TST
Age (years)	41 (29–52)***	49 (41–61)
Male (%)	41.7	44.0
BMI (kg/m^2)	27.3 (24.0–31.8)	27.0 (23.8–31.9)
ESS	9 (5–13)***	5 (3–8)
TST (minutes)	403 (374–429)***	292 (257–313)
N1%	9.7 (5.8–14.6)***	15.7 (9.0–25.0)
N2%	53.0 (46.2–60.1)	53.3 (44.0–62.3)
N3%	18.0 (12.0–23.0)	16.4 (6.1–25.4)
REM%	17.6 (12.8–21.9)***	9.8 (4.6–16.8)
Efficiency (%)	89 (82–93)***	65 (56–73)
SL (minutes)	4.5 (1.5–11.5)***	10.5 (4.5–32.3)
PLMI (1/hour)	6.5 (2.0–17.0)***	13.9 (4.5–34.1)
HR–wake	61.0**	64.9
HR–N1	62.3**	64.6
HR–N2	61.7**	64.9
HR–N3	64.0*	67.4
HR–REM	63.3*	67.8
Depression (%)	32.6	39.5
Anxiety (%)	35.8	45.0
HTN (%)	16.6*	27.5
COPD (%)	1.4	0.9
CAD (%)	1.0**	6.4
CHF (%)	0.6*	3.7
DM (%)	4.9	9.2
Stroke (%)	1.4	3.7
N1 LF	6.3 (5.1–7.4)	6.3 (5.0–7.7)
N1 HF	5.7 (4.4–7.0)	5.5 (3.9–7.1)
N1 HF%	47.6 (41.7–55.1)	45.8 (40.3–52.2)
N1 ratio	1.1 (0.8–1.4)	1.2 (0.9–1.5)
N2 LF	8.5 (7.4–9.9)	8.7 (7.2–10.0)
N2 HF	7.6 (6.2–9.1)	7.5 (6.3–9.2)
N2 HF%	46.7 (41.0–52.2)	45.3 (40.1–51.6)
N2 ratio	1.2 (0.9–1.5)	1.3 (1.0–1.6)
N3 LF	8.7 (7.2–10.6)	8.7 (6.8–10.9)
N3 HF	9.1 (7.0–11.6)	9.6 (6.6–12.4)
N3 HF%	51.0 (45.4–56.2)	48.4 (44.7–58.3)
N3 ratio	1.0 (0.8–1.3)	1.1 (0.7–1.3)
REM LF	8.0 (6.5–9.6)	7.2 (5.8–9.0)
REM HF	6.3 (4.7–8.0)	5.4 (3.8–7.0)
REM HF%	43.4 (38.3–48.4)	42.6 (35.7–49.5)
REM ratio	1.3 (1.1–1.7)	1.4 (1.0–1.8)
W LF	5.9 (4.6–7.8)	6.8 (5.2–8.3)
W HF	5.5 (3.8–8.2)	6.5 (4.4–9.1)
W HF%	47.5 (41.3–52.6)	46.0 (42.9–51.7)
W ratio	1.2 (0.9–1.5)	1.3 (1.0–1.5)

Notes: Data are median (IQR) or percentage. Bold indicates significance:

* P<0.05,

** P<0.001, and

*** P<0.0001.

Abbreviations: BMI, body mass index; CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; ESS, Epworth Sleepiness Scale; HF, high frequency; HR, heart rate; HTN, hypertension; LF, low frequency; PLMI, periodic limb movement index; REM, rapid eye movement; SL, sleep latency; TST, total sleep time; W, wake.

Figure S1 Examples of HR slope assessments from clinical PSGs.

Notes: In (A) and (B), the scored hypnogram is shown above the HR tracing derived from the pulse oximetry signal as visualized through the Grass software. The HR units (Y-axis) are in beats per minute. The color scheme of the stages is the same as in Figure 1 of the main text. Stages are indicated on the Y-axis. Time base is given for an 1 hour increment (and hash marks on the X-axis are 30 minutes apart). For each sleep–wake stage bout of 35 minutes (“stable” bouts), the calculated best fit line is super-imposed on the HR trace (black lines).

Abbreviations: HR, heart rate; PSGs, polysomnography; REM, rapid eye movement; W, wake.

Figure S2 Correlations with TST and with insomnia symptoms.

Notes: (A) Significant correlations above the prespecified minimum of >|0.1| for the PSG-derived TST value. (B) Significant correlations above the prespecified minimum of >|0.1| for insomnia symptoms (“Methods” section).

Abbreviations: CHF, congestive heart failure; ESS, Epworth Sleepiness Scale; HF, high frequency; HR, heart rate; HRV, HR variability; HTN, hypertension; hyp, hypnotic; LF, low frequency; MP, misperception; PLMI, periodic limb movement index; PLMS, periodic limb movements in sleep; PSG, polysomnography; Qual, quality; REM, rapid eye movement; RLS, restless legs syndrome; TST, total sleep time; z-drug, zolpidem, zaleplon, eszopiclone.