Although there are other methods to measure ventricular volumes such as MRI and nuclear technologies, they cannot do so instantaneously. Echocardiography can generate an estimate of instantaneous volume using the modified Simpsons rule or "stack of discs". Because it utilizes a single tomographic plane to estimate three dimensional volumes, it has limitations when applied to patients with regional wall motion abnormalities. Therefore, only improvements in conductance technology offer the ability to make these precise mechanical measurements.
One conductance apparatus commercially available is the Cardiac Function Analyzer made by CardioDynamics in the Netherlands. This apparatus includes the Leycom Sigma 5, a device which is used to measure instantaneous volume from a conductance catheter. The Leycom Sigma 5 has been able to generate adequate volume data in ventricular chambers of large animals which are smaller than 150 ml. However, in patients with congestive heart failure, hearts may range from 180 to 500 ml. It has been previously shown (Reprint 1) that the Sigma 5 cannot generate a homogeneous electric field for volumes seen in human heart failure. Furthermore, there is no built in mechanism for the Sigma 5 to correct for current leakage into the surrounding conductive structures such as myocardium. As a result, it significantly underestimates the stroke volume (volume of blood pumped by the failing heart) and overestimates end-systolic and end-diastolic volumes. In reprints 2-5, there was an average 2-fold underestimation of the stroke volume. U.S. Patent to Carlson teaches that parallel conductance (current leakage outside the blood volume i.e., heart muscle) will be constant at different frequencies, so that this term can be excluded (see column 4, item (6)). Gwane et al. J Appl Physiology vol 63, pg 872-876, 1987 teaches that parallel conductance does vary with frequency, while stroke volume is constant. The present invention is based on the discovery that since muscle resistivity does vary with frequency and blood does not, the resistivity ratio of blood and muscle will vary with frequency. Hence, both the field density within the left ventricle and the current leakage to the surrounding heart muscle both vary with frequency. The end result is both stroke volume and parallel conductance varying with frequency, which is in contrast to both the Carlson patent and Gwane paper. The apparatus uses a digitally controlled signal synthesizer to drive any conductance catheter. This results in more consistent control over waveform shape, amplitude, and frequency than known before. The use of the digital synthesizer also allows the user to select any type of waveform over a broad range of frequencies to apply to a conductance catheter. The digital signal synthesizer is a Signametrics Complex DDS Generator. The device can couple with commercially available conductance catheters made by numerous vendors. One includes Millar Instruments in Houston, Tex. They market conductance catheters with an incorporated Mikrotip pressure transducer for small animals including transgenic mice (SPR 719) and humans (SPC 550, 560, and 570).
The ability to delete single genes from small animals (mice and rats) to generate transgenic animals is now possible. This allows the study of the effect of a single gene deletion on the development on congestive heart failure (weak heart muscle) and hypertrophy (thickened heart muscle). Investigators are currently utilizing left ventricular pressure or its first derivative (dP/dt); or dimension and fractional shortening (derived by echocardiography). The problem with these isolated pressure and dimension measurements is that they are altered just by the heart size changes which accompany congestive heart failure and hypertrophy. Conductance catheter pressure-volume measurements miniaturized for the transgenic mouse allows the physiologic endpoint of how weak the heart muscle has become to be accurately determined. See "Cardiac physiology in transgenic mice" by James et al., and another paper demonstrating the technique of conductance PV loops in the mouse (Georgakopoulos et al. Am J Physiology 1998), both of which are incorporated by reference herein.