Robert W. Sullivan

Magnesium metabolism in patients undergoing cardiopulmonary bypass.

Magnesium metabolism was studied in patients undergoing cardiopulmonary bypass. In 12 patients the mean preoperative serum magnesium level of 1.56±0.10 mEq/L fell to abnormal levels in all patients (1.07±0.04 mEq/L; P<0.001). The decrease in serum magnesium that occurred during bypass is explained by dilution of extracellular volume, as there was no significant difference between mean preoperative and bypass extracellular magnesium. The further postoperative fall in serum magnesium was less than predicted on the basis of magnesium excretion and dilution, implying movement of magnesium from intracellular to extracellular sites. Although the level of serum magnesium correlated poorly with cardiac rhythm or gross neuromuscular abnormalities, three patients with resistant ventricular fibrillation were successfully defibrillated after intravenous bolus injections of magnesium sulfate.

Peripheral venous scintillation angiocardiography in determination of left ventricular volume in man.

Abstract Left ventricular end-diastolic volume was determined by cardiac visualization after peripheral venous injection of a gamma-emitting isotope in 10 patients with organic heart disease. The patients included 5 with aortic insufficiency, 2 with aortic stenosis and 3 with cardiomyopathy. Ten millicuries of technetium-99m, 10 mc in a volume of 1 ml, was injected into an antecubital vein. Sequential single plane images in the right anterior oblique projection were displayed on the oscilloscope of an Anger scintillation camera and were recorded on Polaroid film with exposures integrating counts over serial 2-second intervals. These studies were performed in parallel with left ventricular dye-contrast angiography. A spherical object containing 1 mc of isotope diluted in 200 ml of water was photographed at various distances from the scintillation camera to evaluate distortion and to compute magnification factors. Left ventricular end-diastolic volume was then calculated from X-ray and isotope records by the formula V = π 6L M 2 , where L equals the longest measured axis, and M equals the minor axis, bisecting and perpendicular to L. The left ventricular end-diastolic volume measured by the isotope method consistently averaged 9 percent less than that determined by the X-ray method (mean 206 and 227 ml, respectively). The mean difference in left ventricular end-diastolic volume was 21 ml (range 3 to 39 ml). Excellent correlation (r = 0.993) between the 2 methods was observed. Peripheral venous scintillation angiocardiography compares well with left ventriculography in determination of left ventricular end-diastolic volume in man.

Assessment of Quantitative Apex Cardiography A Noninvasive index of Left Ventricular Function

Abstract Quantitative apex cardiography, a noninvasive method for assessment of left ventricular function, is based upon the close relation observed between the interval from the onset of ventricular depolarization to the preejection peak of the first derivative of the apex cardiogram (R todAdt) and the interval from onset of ventricular depolarization to the peak of the first derivative of the left ventricular pressure pulse (R to LVdPdt). In 12 normal subjects R todAdt varied directly with the R-R interval with a mean of 66 msec. A rate-corrected index, R todAdt√RR, separated normal subjects (72 ± 12) from those with idiopathic hypertrophic subaortic stenosis (57 ± 15) or left ventricular failure (122 ± 23). When R todAdt was compared with hemodynamic and angiographic indexes of left ventricular function in 23 patients studied at diagnostic cardiac catheterization, the following statistically significant correlations were obtained: Ejection fraction (r = −0.81), R to left ventricular dPdt (r = +0.79), Vmax(r = −0.62), peak left ventricular dPdt (r = −0.66), left ventricular end-diastolic pressure (r = +0.49), and left ventricular end-diastolic volume (r = +0.64). These data support the use of quantitative apex cardiography for screening or serial clinical studies of left ventricular function.

A novel fibroblast activation inhibitor attenuates left ventricular remodeling and preserves cardiac function in heart failure

Cardiac fibroblasts are critical mediators of fibrotic remodeling in the failing heart and transform into myofibroblasts in the presence of profibrotic factors such as transforming growth factor-β. Myocardial fibrosis worsens cardiac function, accelerating the progression to decompensated heart failure (HF). We investigated the effects of a novel inhibitor (NM922; NovoMedix, San Diego, CA) of the conversion of normal fibroblasts to the myofibroblast phenotype in the setting of pressure overload-induced HF. NM922 inhibited fibroblast-to-myofibroblast transformation in vitro via a reduction of activation of the focal adhesion kinase-Akt-p70S6 kinase and STAT3/4E-binding protein 1 pathways as well as via induction of cyclooxygenase-2. NM922 preserved left ventricular ejection fraction ( P < 0.05 vs. vehicle) and significantly attenuated transverse aortic constriction-induced LV dilation and hypertrophy ( P < 0.05 compared with vehicle). NM922 significantly ( P < 0.05) inhibited fibroblast activation, as evidenced by reduced myofibroblast counts per square millimeter of tissue area. Picrosirius red staining demonstrated that NM922 reduced ( P < 0.05) interstitial fibrosis compared with mice that received vehicle. Similarly, NM922 hearts had lower mRNA levels ( P < 0.05) of collagen types I and III, lysyl oxidase, and TNF-α at 16 wk after transverse aortic constriction. Treatment with NM922 after the onset of cardiac hypertrophy and HF resulted in attenuated myocardial collagen formation and adverse remodeling with preservation of left ventricular ejection fraction. Future studies are aimed at further elucidation of the molecular and cellular mechanisms by which this novel antifibrotic agent protects the failing heart. NEW & NOTEWORTHY Our data demonstrated that a novel antifibrotic agent, NM922, blocks the activation of fibroblasts, reduces the formation of cardiac fibrosis, and preserves cardiac function in a murine model of heart failure with reduced ejection fraction.