Abnormal heart rate regulation in murine hearts with familial hypertrophic cardiomyopathy-related cardiac troponin T mutations

Abstract

Mutations in cardiac troponin T (cTnT), Δ160E and R92Q, have been linked to familial hypertrophic cardiomyopathy (FHC), and some studies have indicated that these mutations can lead to a high incidence of sudden cardiac death in the relative absence of significant ventricular hypertrophy. Alterations in autonomic function have been documented in patients with hypertrophic cardiomyopathy. We hypothesize that alterations in autonomic function may contribute to mutation-specific clinical phenotypes in cTnT-related FHC. Heart rate (HR) variability (HRV) has been used to assess autonomic function from an electrocardiograph. Nontransgenic, Δ160E, or R92Q mice were implanted with radiofrequency transmitters to obtain continuous electrocardiograph recordings during 24-h baseline and 30-min recordings after β-adrenergic receptor drug injections. Although Δ160E mice did not differ from nontransgenic mice for any 24-h HRV measurements, R92Q mice had impaired HR regulation, as measured by a decrease in the SD of the R-R interval, a decrease in the low frequency-to-high frequency ratio, a decrease in normalized low frequency, and an increase in normalized high frequency. β-Adrenergic receptor density measurements and HRV analysis after drug injections did not reveal any significant differences for Δ160E or R92Q mice versus nontransgenic mice. Arrhythmia analysis revealed both an increased incidence of heart block in R92Q mice at baseline and frequency of premature ventricular contractions after isoproterenol injections in Δ160E and R92Q mice. In addition, Δ160E and R92Q mice exhibited a prolonged P duration after drug injections. Therefore, between two independent and clinically severe cTnT mutations within the same functional domain, only R92Q mice exhibited altered autonomic function, whereas both mutations demonstrated abnormalities in conduction and ventricular ectopy.

Fig. 1.

Histograms of mean R-R intervals (RR_mean) demonstrating differences in macroscopic heart rate (HR) variabilitiy (HRV) of 24-h baseline recordings calculated in 2-min average segments. n = 6 nontransgenic (non-TG), Δ160E, and R92Q mice.

Fig. 2.

Time-domain measures of HRV of 24-h baseline recordings. A: SD of all normal R-R intervals (SDNN). B: SD of averages of normal R-R intervals in all 2-min segments of the entire recording (SDANN). Values are means ± SE. N.S., not significant. *P < 0.05 vs. non-TG mice.

Fig. 3.

Frequency-domain measures of HRV of 24-h baseline recordings. A: total power (TP; 0.0–5 Hz). B: very low frequency (VLF; 0.0–0.15 Hz). C: normalized low frequency (nLF). D: normalized high frequency (nHF). E: ratio of low frequency (0.15–1.5 Hz) to high frequency (1.5–5 Hz) (LF/HF). Values are means ± SE. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. non-TG mice.

Fig. 4.

HR and time measures of HRV after saline, isoproterenol, and propranolol injections (n = 8 non-TG, 6 Δ160E, and 5 R92Q mice). A: HR. B: RR_mean. C: SDNN. D: SDANN. The inset shows averaged representative HR recordings of non-TG, Δ160E, or R92Q mice over the 30-min segment after each saline, isoproterenol, or propranolol injection. Values are means ± SE. *P < 0.05 and ***P < 0.001 vs. the saline counterpart; #P < 0.05 and ##P < 0.01 vs. non-TG mice within drug groups.

Fig. 5.

Frequency-domain measures of HRV after saline, isoproterenol, and propranolol injections. A: TP. B: VLF. C: nLF. D: nHF. E: LF/HF. Values are means ± SE. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. the saline counterpart; ##P < 0.01 vs. non-TG mice within drug groups.

Fig. 6.

A and B: representative 1-s ECG traces of a premature ventricular contraction (PVC; A) and heart block (B). C and D: PVC and heart block incidence rates after saline, isoproterenol, and propranolol injections. C: PVC/30 min; D: heart block/30 min. Values are means ± SE. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. the saline counterpart; #P < 0.05 and ##P < 0.01 vs. non-TG mice within drug groups.