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Background: Preclinical studies suggest granulocyte-colony stimulating factor (G-CSF) holds promise for treating ischemic heart disease; however; its clinical safety and efficacy in this setting remain unclear. We elected to evaluate the safety and efficacy of G-CSF administration in patients with refractory "no-option" ischemic heart disease., Methods: Twenty patients (18 males, 2 females, mean age 62.4 years) were enrolled and underwent baseline cardiac ischemia assessment (CA) (angina questionnaire, exercise stress test [EST], technetium Tc 99m sestamibi and dobutamine-stress echocardiographic imaging). Patients then received open-label G-CSF commencing at 10 microg/kg SC for 5 days, with an EST on days 4 and 6 (to facilitate myocardial cytokine generation and stem cell trafficking). After 3 months, CA and the same regimen of G-CSF+ESTs were repeated but, in addition, leukapheresis and a randomized double-blinded intracoronary infusion of CD133+ or unselected cells were performed. Final CA occurred 3 months thereafter., Results: There were no deaths, but only 16 patients were permitted to complete the study. Eight events fulfilled prespecified "adverse event" criteria, including 4 troponin I-positive events and 2 episodes of thrombocytopenia. Also, frequent minor troponin I-positive events (troponin I<0.9 microg/L) were observed, which did not meet adverse event criteria. The administration of consecutive cycles of G-CSF resulted in stepwise improvements in anginal frequency, EST performance, and Duke treadmill scores (all P<.005). However, from baseline to final follow-up, technetium Tc 99m sestamibi and dobutamine-stress echocardiographic results were unchanged., Conclusions: Granulocyte-colony stimulating factor administration was associated with improvement in a range of subjective outcomes. However, adverse events were common, and objective measures of cardiac perfusion/ischemia were unchanged.

Objective: To determine the effect of acute increments in left ventricular afterload on the stroke work output of the right ventricle in vivo., Methods: After pharmacologic attenuation of autonomic reflexes, left and right ventricular pressure-volume data were obtained in 9 conscious dogs during vena caval occlusions performed before and during aortic constriction., Results: The relationship between right ventricular stroke work and end-diastolic volume during vena caval occlusion was highly linear (r = 0.97 +/- 0.02), but the slope decreased by 20% +/- 13% during aortic constriction sufficient to increase left ventricular mean ejection pressure by 25% +/- 14% (P <.05). The volume-axis intercept remained constant. Similarly, the slope of the linear relationship between right ventricular free wall regional segment work and end-diastolic segment length declined by 22% +/- 10% during aortic constriction (P <.05), without significant change in the length-axis intercept. The reduction in both global and regional right ventricular stroke work at any given preload with increased left ventricular afterload was due entirely to decreased right ventricular stroke volume and free wall shortening, because right ventricular mean ejection pressure was unchanged. Additional experiments were performed in 5 open-chest dogs to produce a greater reduction in left ventricular free wall shortening than observed with aortic constriction by transient constriction of the left circumflex coronary artery. However, this intervention had no effect on right ventricular free wall segment work output., Conclusion: Increased left ventricular afterload decreases global and regional right ventricular stroke work at any given preload, a direct, negative systolic ventricular interaction.

Objective: Our goal was to examine the validity of unidimensional indexes of right ventricular contractile performance in vivo., Methods: Unidimensional indexes and global measurements of right ventricular volume and contractile performance were compared in 6 conscious dogs. Vena caval occlusions were performed before (control) and during pulmonary arterial or aortic constriction., Results: Moderately strong relationships were demonstrated between right ventricular septal-free wall indexes and global measurements of right ventricular end-diastolic and end-systolic volumes, stroke volume, stroke work, and the slope of the preload recruitable stroke work relationship, respectively, under control conditions (mean r (2) range 0.69-0.94). These relationships were shifted significantly, however, by increased right ventricular afterload. Increased left ventricular afterload significantly shifted the relationships between right ventricular septal-free wall dimensions and end-diastolic and end-systolic volumes. Relationships between the corresponding regional right ventricular free wall segmental indexes and global measurements under control conditions were weaker (mean r (2) range 0.12-0.65) and were significantly more sensitive to distortion by both increased right and left ventricular afterload, the effects of which were generally in opposite directions. These observations are consistent with significant ventricular interactive effects on the relationship between single right ventricular dimensions and right ventricular volume., Conclusion: Unidimensional right ventricular measurements are not reliable surrogates for right ventricular volume when assessing right ventricular contractile performance in the intact heart.

Objective: Cardiac failure as a result of valvular heart disease remains a major clinical problem that frequently leads to ventricular dysfunction, myocardial failure, and even death. The development of irreversible myocardial damage may be especially insidious in volume overload as a result of aortic or mitral regurgitation., Methods and Results: Left ventricular wall volume, ventricular function, and myocardial performance were assessed in 10 chronically instrumented conscious dogs before and after creation of aortic regurgitation. Left ventricular wall volume was measured by serial echocardiography. Left ventricular function was assessed by total cardiac output, stroke work, the slope of the Frank-Starling relationship, and the slope of the end-systolic pressure-volume relationship. Myocardial performance was assessed by the slope of the myocardial power output versus end-diastolic strain relationship. End-diastolic wall stress and volume both increased acutely and remained elevated after creation of aortic regurgitation. Peak systolic wall stress increased initially (1 to 3 weeks) from 336 +/- 30 to 369 +/- 55 mm Hg but returned to control values as left ventricular wall volume increased from 78 +/- 13 to 88 +/- 16 ml after development of compensatory hypertrophy. Left ventricular systolic function remained constant or increased and was maintained initially by increased myocardial performance, which returned to baseline levels after the development of compensatory hypertrophy., Conclusions: Myocardial performance and ventricular function vary independently in aortic regurgitation. Measures of myocardial performance such as the myocardial power output versus end-diastolic strain relationship may be useful in clinical assessment of aortic regurgitation.

Doppler measurement of left atrial appendage (LAA) blood velocity during transesophageal echocardiography has been proposed as a method of assessing LAA contractile function and thromboembolic risk. Clinical and echocardiographic determinants of five LAA Doppler blood velocity patterns were examined in 40 patients with a history of atrial fibrillation (AF), in 10 control subjects, and in 5 patients aged

To develop a method for quantitative analysis of regional left ventricular function from transesophageal two-dimensional echocardiograms, we conducted studies 10 and 20 minutes after induction of anesthesia in 16 patients with normal hearts who were undergoing minor orthopedic operations. Wall thickening was measured with the centerwall method along 100 chords drawn perpendicular to a line constructed around the center of the ventricular wall, midway between the endocardial and epicardial contours. Thickening, either normalized by the length of the end-diastolic perimeter or expressed as a percentage of the end-diastolic wall thickness at each chord, was compared with measurements of endocardial motion. Wall motion was relatively diminished in the anteroseptal region and enhanced on the contralateral wall, but wall thickening was homogeneous throughout the contour. Normalized wall thickening was significantly less variable (standard deviation/mean, 0.47 +/- 0.13) in the normal population than were either percent wall thickening (0.53 +/- 0.012) or wall motion (0.51 +/- 0.09) (p less than 0.005 for both comparisons). There was no significant change in regional or global function between 10 minutes and 20 minutes after the induction of anesthesia. In summary, normalized wall thickening as a parameter of regional left ventricular function is more homogeneous and less variable in subjects with normal hearts than is endocardial motion because wall thickening measurements are not subject to cardiac translocation artifacts. This low variability suggests that normalized wall thickening measured by the centerwall method may prove particularly useful for intraoperative and postoperative monitoring of regional left ventricular function by transesophageal echocardiography in patients undergoing both cardiac and noncardiac surgical procedures.

Right ventricular failure is a leading cause of death in patients who require the left ventricular assist device. Previous reports suggested right ventricular functional deterioration during left ventricular assist but lacked a method by which right ventricular function could be quantified adequately. This study examined the effects of left ventricular volume unloading on right ventricular systolic function by means of the stroke work/end-diastolic volume relationship, a load-insensitive index of myocardial performance. In 12 anesthetized open-chested dogs, right ventricular and left ventricular pressures were measured with micromanometers while ultrasonic dimension transducers measured left and right ventricular orthogonal diameters. Left ventricular unloading was accomplished with left atrial-to-femoral artery bypass with a centrifugal pump. Data were recorded during transient vena caval occlusion in the control state and with maximal left ventricular unloading by full support by the left ventricular assist device. Modified ellipsoidal geometry was used to calculate simultaneous biventricular volumes, and linear regression analysis of right ventricular stroke work versus end-diastolic volume was used to quantify right ventricular systolic function. Average slope and x intercept of this relationship under control conditions were 2.2 +/- 0.3 X 10(4) erg/ml and 10.7 +/- 5.0 ml, respectively. During full support by the left ventricular assist device (mean flow rate, 2.4 +/- 0.3 L/min), left ventricular end-diastolic volume decreased by 31% (p less than 0.01), left ventricular septal-free wall diameter decreased by 7% (p less than 0.001), and rate of rise of right ventricular peak positive pressure declined by 13% (p less than 0.05). The corresponding slope and x intercept of the right ventricular stroke work/end-diastolic volume relationship during full unloading of left ventricular assist device were 2.3 +/- 0.3 X 0.3 X 10(4) erg/ml and 14.3 +/- 4.8 ml, respectively; these values were not significantly different from control values (p greater than 0.5). Additionally, analysis of right ventricular end-diastolic pressure-volume relationships suggested improved right ventricular chamber compliance, although the effects were small and did not reach statistical significance (p = 0.10). These data imply that marked alterations in biventricular geometry accompanying left ventricular volume unloading by the left ventricular assist device in a normal heart do not significantly alter right ventricular performance characteristics.

Severe mitral regurgitation caused by acute myocardial infarction has been a particularly difficult management problem with disappointing clinical results. Over a 75-month period, ending March 31, 1987, 611 patients underwent mitral valve operations at Duke University Medical Center. Within this group, 55 patients had clearly defined ischemic mitral regurgitation, and 37 of these required emergency operations. Thirty-one of the 55 patients had isolated posterior papillary muscle dysfunction, nine had papillary muscle rupture, and 15 had severe ventricular dysfunction and generalized annular dilatation. Thirty-two patients were treated with primary mitral valve replacement, and 23 had mitral valve repair. In 18, repair was accomplished by a transventricular approach, combining the techniques of commissural annuloplasty, papillary muscle shortening or reimplantation, and infarct exclusion. Transventricular mitral valve repair proved to be safe, expeditious, and effective in restoring valve competence. Although the repair and replacement groups were similar with respect to all relevant baseline characteristics, improved operative survival was observed after valve repair, as compared to replacement, both for the overall group (p = 0.03) and for acute papillary muscle dysfunction (p = 0.05). These data suggest that a policy of predominant mitral valve repair, when appropriately applied in patients with ischemic mitral regurgitation, offers the potential for improving therapeutic results.