Increased susceptibility of spontaneously hypertensive rats to ventricular tachyarrhythmias in early hypertension

Abstract

Key pointsr Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation.r Whether hypertension in its early stage is associated with an increased risk of ventricular tachyarrhythmias is not known.r Based on experiments performed at the cellular and whole heart levels, we show that, even early in chronic hypertension, the hypertrophied and fibrotic ventricles of spontaneously hypertensive rats aged 5 to 6 months have already developed increased stress-induced arrhythmogenicity, and this increased susceptibility to ventricular arrhythmias is primarily a result of tissue remodelling rather than cellular electrophysiological changes.r Our findings highlight the need for early hypertension treatment to minimize myocardial fibrosis, ventricular hypertrophy, and arrhythmias.Abstract Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation (VT/VF). We hypothesized that, in early hypertension, the susceptibility to stress-induced VT/VF increases. We compared the susceptibility of 5-to 6-month-old male spontaneously hypertensive rats (SHR) and age/sex-matched normotensive rats (NR) to VT/VF during challenge with oxidative stress (H 2 O 2 ; 0.15 mmol l −1 ). We found that only SHR hearts exhibited left ventricular fibrosis and hypertrophy. H 2 O 2 promoted VT in all 30 SHR but none of the NR hearts. In 33% of SHR cases, focal VT degenerated to VF within 3 s. Simultaneous voltage-calcium optical mapping of Langendorff-perfused SHR hearts revealed that H 2 O 2 -induced VT/VF arose spontaneously from focal activations at the base and mid left ventricular epicardium. Microelectrode recording of SHR hearts showed that VT was initiated by early afterdepolarization (EAD)-mediated triggered activity. However, despite the increased susceptibility of SHR hearts to VT/VF, patch clamped isolated SHR ventricular myocytes developed EADs and triggered activity to the same extent as NR ventricular myocytes, except with larger EAD amplitude. During the early stages of hypertension, when challenged with oxidative stress, SHR hearts showed an increased ventricular arrhythmogenicity that stems primarily from tissue remodelling (hypertrophy, fibrosis) rather than cellular electrophysiological changes. Our findings highlight the need for early hypertension treatment to minimize myocardial fibrosis, ventricular hypertrophy, and arrhythmias. NR, normotensive rats; PA peak vel, pulmonary artery peak velocity; (P)CL, (pacing) cycle length; PW, posterior wall; P-ECG, pseudo-electrocardiogram; RV, right ventricle; RWT, relative wall thickness; SHR, spontaneously hypertensive rats; SHHF, spontaneously hypertensive heart failure; SBP, systolic blood pressure; VT/VF, ventricular tachycardia and fibrillation.

The impact of 21-hydroxylase deficiency on cardiac repolarization changes in children with 21-hydroxylasedeficient congenital adrenal hyperplasia

“…These effects may be due to activated glucocorticoid and mineralocorticoid receptors on arterial and heart tissue, increased contractility of vascular tissue by enhancing sensitivity to noradrenaline and reduced endothelium dependent vasodilation. 26 Ventricular cardiac arrhythmias have been considered as one of the first electrocardiographic abnormalities to appear in early hypertensive rats 12 . Increased risk of high systolic blood pressure has been attributed to weight, BMI, duration of hydroxycortisone treatment, dyslipidemia, and insulin resistance.…”

“…We reported increased susceptibility of 21-hydroxylase deficiency to ventricular cardiac arrhythmias and death in uncontrolled children and adolescents. Nguyen et al 12 found that interstitial myocardial fibrosis due to early hypertension was associated with adverse structural and electrical remodeling changes. Nguyen et al 12 hypothesized that basic differences in intracellular calcium cycling dynamics caused early after depolarization in ventricular myocytes from spontaneously hypertensive rats.…”

“…Nguyen et al 12 found that interstitial myocardial fibrosis due to early hypertension was associated with adverse structural and electrical remodeling changes. Nguyen et al 12 hypothesized that basic differences in intracellular calcium cycling dynamics caused early after depolarization in ventricular myocytes from spontaneously hypertensive rats. Tp-e dispersion affected by levels of systolic blood pressure was significantly higher in the patient group and positively correlated with systolic blood pressure.…”

“…Lifelong glucocorticoid treatment in patients with 21 hydroxylase deficiency may result in increased cardiovascular risk factors such as, obesity, insulin resistance with type 2 diabetes (T2DM), and hypertension. The early stage of hypertension was associated with an increased risk of myocardial fibrosis, ventricular hypertrophy and arrhythmias 12 . Glucocorticoids given in supraphysiological dose, play a role in myocardial fibrosis and cardiac hypertrophy with mineralocorticoid receptor (MR) activation.…”

Synergism between Enhanced Late Inward Currents and Tissue Fibrosis in the Initiation of Spontaneous Ventricular Tachyarrhythmias

“…We tested the synergism hypothesis in fibrotic rat and rabbit hearts by oxidative stress-induced rises in the late Na and Ca inward depolarizing currents with hydrogen peroxide or angiotensin II [14,18–20]. While the fibrotic hearts maintained normal rhythm when exposed to normal physiological solution, however, upon induction of enhanced late Na and Ca currents with oxidative [11,14] or metabolic stress [21] a synergism developed that promoted VT/VF in greater than 90 percent of the hearts studied [11,12].…”