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Cardiovascular function following acute volume overload for hydrodynamic gene delivery to the liver
G J Sawyer1, X Dong, M Whitehorne
1Department of Hepatology and Transplantation, King's College London School of Medicine, The Rayne Institute, and Department of Clinical Perfusion Sciences, King's College Hospital, London, UK.
Gene Therapy
|June 15, 2007
Summary
Hydrodynamic gene delivery to the liver causes acute cardiovascular stress, including dangerous drops in blood pressure and heart rhythm abnormalities. The liver may act as a volume sink, but high volumes lead to severe cardiac events.
Area of Science:
- Cardiovascular Physiology
- Gene Therapy
- Hepatology
Background:
- Hydrodynamic gene delivery is a promising nonviral gene therapy for liver diseases.
- Acute cardiovascular volume overload is a significant barrier to clinical translation.
- The physiological impact of rapid, high-volume infusions into the inferior vena cava (IVC) is not well understood.
Purpose of the Study:
- To investigate the cardiovascular and electrocardiographic (ECG) effects of varying infusion volumes of DNA solution into the IVC.
- To assess the potential role of the liver as a volume sink during hydrodynamic gene delivery.
- To evaluate the impact of vagal blockade and electrolyte balance on the observed physiological responses.
Main Methods:
- Infusion of pGL3 plasmid solutions at 100 ml/min, representing 1%, 2%, 4%, 6%, and 8% of body weight, into the IVC of DA rats.
- Continuous monitoring of central venous pressure (CVP), arterial pressure, pulse, and ECG.
- Administration of atropine for vagal blockade and Ringer's solution to manage electrolyte balance.
Main Results:
- All infusion volumes, starting from 1%, induced rapid decreases in blood pressure and pulse, accompanied by ECG abnormalities like ectopic beats and QRS widening.
- Higher volumes (4% and above) suggested a volume-sink effect by the liver, moderating immediate overload.
- The 6% and 8% volumes resulted in severe, prolonged hypotension, bradycardia, and significant cardiac electrical disturbances, including electromechanical dissociation.
- Vagal blockade and electrolyte management did not prevent or mitigate these adverse cardiovascular events.
Conclusions:
- Rapid, high-volume infusions into the IVC, even at low percentages of body weight, pose substantial risks of acute cardiovascular compromise.
- The liver's capacity as a volume sink is limited, and excessive volumes can lead to life-threatening cardiac events.
- Current strategies like vagal blockade or electrolyte correction are insufficient to counteract the severe hemodynamic and electrophysiologic effects of hydrodynamic gene delivery.
