The Functional Consequences of Sodium Channel NaV1.8 in Human Left Ventricular Hypertrophy

Figures

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  Figure 1. Regulation of NaV1.8 and NaV1.5 expression in hypertrophy. (A) Western blots were performed utilizing left ventricular human tissue homogenates. (B) Densitometry data of NaV1.8 and NaV1.5 show a significant up‐regulation of NaV1.8 and down‐regulation of NaV1.5. GAPDH was used as an internal loading control in all blots [NF: n = 12; and left ventricular hypertrophy (LVH): n = 12]. (C) Real‐time quantitative PCR showing the relative mRNA expression of NaV1.8/GAPDH in left ventricle of human NF (n = 10) and LVH (n = 5). *P ≤ 0.05 and **P ≤ 0.01 vs. NF. Student's t‐test. Data shown as mean ± standard error of the mean and individual values.

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  Figure 2. (A) Original traces and (B) data showing individual and mean values ± standard error of the mean of INaL in human ventricular cardiomyocytes isolated from left ventricular hypertrophy patients (control: n = 8 cells; A‐803467: n = 7 cells; PF‐01247324: n = 7 cells). *P ≤ 0.05. One‐way analysis of variance and Bonferroni's post‐test.

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  Figure 3. (A) Original action potential recording (0.5 Hz) and (B) data showing individual and mean values ± standard error of the mean of APD90 in left ventricular cardiomyocytes from patients with left ventricular hypertrophy. A‐803467 or PF‐01247324 paced at 0.5 and 1 Hz (n = 5 cells and n = 4 cells, respectively; *P ≤ 0.05 vs. control). Two‐way repeated measures analysis of variance and Bonferroni's post‐test. All the action potential duration (APD) measurements were performed pairwise by wash‐in.

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  Figure 4. (A) Individual and mean values ± standard error of the mean showing upstroke velocity of action potential in control and drug groups from left ventricular hypertrophy cardiomyocytes. (B) Data showing individual and mean values ± standard error of the mean of action potential amplitude (APA) measurements from isolated human left ventricular hypertrophy cardiomyocytes. (C) Graph shows the resting membrane potential (RMP) of cardiomyocytes measured under control condition and drug treatments (PF‐01247324: n = 5 cells; and A‐804367: n = 4 cells). All measurements were performed pairwise by wash‐in. Paired Student's t‐test was performed.

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  Figure 5. (A) Representative line scan images and (B) calcium spark frequency (CaSpF) in left ventricular cardiomyocytes from patients with left ventricular hypertrophy under control condition and NaV1.8 inhibition. Pre‐incubation with either A‐803467 or PF‐01247324 resulted in a significant decrease of CaSpF in hypertrophy compared with control. (C) Mean values of spark duration and (D) spark amplitude of cardiomyocytes. (E) Calculated full SR‐Ca2+ leak in left ventricular cardiomyocytes from left ventricular hypertrophy patients (control: n = 145; A‐803467: n = 124 cells; PF‐01247324: n = 91 cells). Data shown as mean ± standard error of the mean. One‐way analysis of variance and Bonferroni's post‐test. *P ≤ 0.05, **P ≤ 0.01.