Increased inducibility of ventricular tachycardia and decreased heart rate variability in a mouse model for type 1 diabetes

Effect of pravastatin

Mohammad Rajab, Hongwei Jin, Charles M. Welzig, Alfred Albano, Mark Aronovitz, Yali Zhang, Ho Jin Park, Mark S. Link, Sami F. Noujaim, Jonas B. Galper

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Although a reduction in the high-frequency (HF) component of heart rate variability (HRV) is a major complication of diabetes and a risk factor for sudden death, its relationship to ventricular tachycardia (VT) is unknown. We developed a mouse model for the study of VT and its relationship to changes in HRV in the Akita type 1 diabetic mouse. Programmed ventricular stimulation of anesthetized mice demonstrated that Akita mice were more inducible for VT compared with wild-type mice: 78.6% versus 28.6% (P = 0.007). Optical mapping of perfused hearts demonstrated multifocal breakthroughs that occasionally gave rise to short-lived rotors consistent with focal initiation and maintenance of VT. Treatment of Akita mice with pravastatin, which had been previously shown clinically to decrease ventricular ectopy and to increase HRV, decreased the inducibility of VT: 36.8% compared with 75.0% with placebo treatment (P= 0.022). The HF fraction of HRV was reduced in Akita mice (48.6 ±5.2% vs. 70.9 ± 4.8% in wild-type mice, P = 0.005) and was increased compared with placebo treatment in pravastatin-treated mice. Pretreatment of Akita mice with the muscarinic agonist carbamylcholine or the β-adrenergic receptor blocker propranolol decreased the inducibility of VT (P 0.001). In conclusion, the increased inducibility of focally initiated VT and reduced HF fraction in Akita mice were partially reversed by both pravastatin treatment and pharmacologic reversal of parasympathetic dysfunction. In this new animal model for the study of the pathogenesis of VT in type 1 diabetes, pravastatin may play a role in the prevention of VT by attenuating parasympathetic dysfunction.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume305
Issue number12
DOIs
StatePublished - Dec 15 2013

Fingerprint

Pravastatin
Ventricular Tachycardia
Type 1 Diabetes Mellitus
Heart Rate
Placebos
Muscarinic Agonists
Adrenergic Antagonists
Carbachol
Diabetes Complications
Therapeutics
Sudden Death
Propranolol
Adrenergic Receptors
Animal Models
Maintenance

Keywords

  • Secondary effects of diabetes
  • Statins
  • Type 1 diabetes
  • Ventricular tachycardia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Increased inducibility of ventricular tachycardia and decreased heart rate variability in a mouse model for type 1 diabetes : Effect of pravastatin. / Rajab, Mohammad; Jin, Hongwei; Welzig, Charles M.; Albano, Alfred; Aronovitz, Mark; Zhang, Yali; Park, Ho Jin; Link, Mark S.; Noujaim, Sami F.; Galper, Jonas B.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 305, No. 12, 15.12.2013.

Research output: Contribution to journalArticle

Rajab, Mohammad ; Jin, Hongwei ; Welzig, Charles M. ; Albano, Alfred ; Aronovitz, Mark ; Zhang, Yali ; Park, Ho Jin ; Link, Mark S. ; Noujaim, Sami F. ; Galper, Jonas B. / Increased inducibility of ventricular tachycardia and decreased heart rate variability in a mouse model for type 1 diabetes : Effect of pravastatin. In: American Journal of Physiology - Heart and Circulatory Physiology. 2013 ; Vol. 305, No. 12.
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abstract = "Although a reduction in the high-frequency (HF) component of heart rate variability (HRV) is a major complication of diabetes and a risk factor for sudden death, its relationship to ventricular tachycardia (VT) is unknown. We developed a mouse model for the study of VT and its relationship to changes in HRV in the Akita type 1 diabetic mouse. Programmed ventricular stimulation of anesthetized mice demonstrated that Akita mice were more inducible for VT compared with wild-type mice: 78.6{\%} versus 28.6{\%} (P = 0.007). Optical mapping of perfused hearts demonstrated multifocal breakthroughs that occasionally gave rise to short-lived rotors consistent with focal initiation and maintenance of VT. Treatment of Akita mice with pravastatin, which had been previously shown clinically to decrease ventricular ectopy and to increase HRV, decreased the inducibility of VT: 36.8{\%} compared with 75.0{\%} with placebo treatment (P= 0.022). The HF fraction of HRV was reduced in Akita mice (48.6 ±5.2{\%} vs. 70.9 ± 4.8{\%} in wild-type mice, P = 0.005) and was increased compared with placebo treatment in pravastatin-treated mice. Pretreatment of Akita mice with the muscarinic agonist carbamylcholine or the β-adrenergic receptor blocker propranolol decreased the inducibility of VT (P 0.001). In conclusion, the increased inducibility of focally initiated VT and reduced HF fraction in Akita mice were partially reversed by both pravastatin treatment and pharmacologic reversal of parasympathetic dysfunction. In this new animal model for the study of the pathogenesis of VT in type 1 diabetes, pravastatin may play a role in the prevention of VT by attenuating parasympathetic dysfunction.",
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AU - Jin, Hongwei

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AU - Albano, Alfred

AU - Aronovitz, Mark

AU - Zhang, Yali

AU - Park, Ho Jin

AU - Link, Mark S.

AU - Noujaim, Sami F.

AU - Galper, Jonas B.

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AB - Although a reduction in the high-frequency (HF) component of heart rate variability (HRV) is a major complication of diabetes and a risk factor for sudden death, its relationship to ventricular tachycardia (VT) is unknown. We developed a mouse model for the study of VT and its relationship to changes in HRV in the Akita type 1 diabetic mouse. Programmed ventricular stimulation of anesthetized mice demonstrated that Akita mice were more inducible for VT compared with wild-type mice: 78.6% versus 28.6% (P = 0.007). Optical mapping of perfused hearts demonstrated multifocal breakthroughs that occasionally gave rise to short-lived rotors consistent with focal initiation and maintenance of VT. Treatment of Akita mice with pravastatin, which had been previously shown clinically to decrease ventricular ectopy and to increase HRV, decreased the inducibility of VT: 36.8% compared with 75.0% with placebo treatment (P= 0.022). The HF fraction of HRV was reduced in Akita mice (48.6 ±5.2% vs. 70.9 ± 4.8% in wild-type mice, P = 0.005) and was increased compared with placebo treatment in pravastatin-treated mice. Pretreatment of Akita mice with the muscarinic agonist carbamylcholine or the β-adrenergic receptor blocker propranolol decreased the inducibility of VT (P 0.001). In conclusion, the increased inducibility of focally initiated VT and reduced HF fraction in Akita mice were partially reversed by both pravastatin treatment and pharmacologic reversal of parasympathetic dysfunction. In this new animal model for the study of the pathogenesis of VT in type 1 diabetes, pravastatin may play a role in the prevention of VT by attenuating parasympathetic dysfunction.

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