William P. Miller

Altered calcium sensitivity of isometric tension in myocyte-sized preparations of porcine postischemic stunned myocardium.

Postischemic ventricular myocardial dysfunction, termed stunning, is characterized by a persistent but ultimately reversible depression of contractile function. The present study was undertaken to investigate the possibilities that reduced contractile force in stunning is due to a decrease in maximal tension-generating capability or to a decrease in the Ca2+ sensitivity of the myofilaments. The experiments combine an in vivo open-chest porcine heart model of stunning (n = 5) with in vitro measures of myocyte myofilament calcium sensitivity from these same hearts. Regional myocardial function in the left anterior descending coronary artery (LAD) perfusion bed of porcine hearts was measured with transmural ultrasonic crystals. The protocol was 45 minutes of low-flow LAD ischemia at 40% of control flow, followed by 30 minutes of postischemic reperfusion at control aerobic flow. Percent systolic wall thickening decreased to 8 +/- 5% of control during ischemia (p < 0.05) and returned to 38 +/- 8% of control in the postischemic stunned state (p < 0.05). Serial endocardial biopsies were obtained from the preischemic and postischemic myocardium in the LAD perfusion bed and from the aerobically perfused myocardium in the circumflex bed. The biopsies were mechanically disrupted, and myocyte-sized preparations of permeabilized myocardium were attached to a force transducer and a length-changing device to allow for direct measurement of steady-state tension-pCa (i.e., -log[Ca2+]) relations. The pCa for half-maximal activation of tension, i.e., pCa50, in LAD myocardium decreased from 5.88 +/- 0.05 before ischemia to 5.69 +/- 0.03 after ischemia (p < 0.05); however, maximal Ca(2+)-activated tension and the slope of the tension-pCa relation were unaffected by the ischemic episode.(ABSTRACT TRUNCATED AT 250 WORDS)

Isometric and Dynamic Contractile Properties of Porcine Skinned Cardiac Myocytes After Stunning

The purpose of this study was to investigate myofibrillar mechanisms of depressed contractile function associated with myocardial stunning. We first tested whether the degree of stunning was directly related to changes in myofilament Ca2+ sensitivity. Variable degrees and durations of low-flow ischemia were followed by 30 minutes of reperfusion in an open-chest porcine model of regional myocardial stunning (n = 27). Ca2+ sensitivity of isometric tension was measured in skinned myocytes obtained from endocardial biopsies taken during control aerobic flow and after 30 minutes of reperfusion. The degree of stunning, as assessed by percent systolic wall thickening, ranged from -3% to 75% of control but did not correlate (r = .11) with changes in pCa50, ie, pCa for half-maximal tension. Only in the group (n = 10) with the most severe level of ischemia was there a significant decrease in pCa50 (from 5.97 +/- 0.06 in the control condition to 5.86 +/- 0.07 after ischemia, P < .05). Less severe levels of ischemia (n = 17) resulted in significant stunning (percent systolic wall thickening, 38 +/- 4% of control) but no change in pCa50. To investigate the possibility that alterations in myofibrillar cross-bridge kinetics contribute to depressed function in stunning, maximum velocity of shortening (Vo) was measured in postischemic myocytes. Vo in postischemic myocytes was reduced to 56 +/- 4% of Vo in control myocytes and was independent both of the degree of stunning (r = .26) and changes in Ca2+ sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular dual-energy digital subtraction angiography: a motion immune digital subtraction technique

Digital subtraction angiography (DSA) allows quantitative analysis of ventricular function via densitometric and parametric imaging techniques. However, DSA is limited by the artifacts in temporal subtraction images that result from patient and cardiac motion. Dual-energy subtraction imaging is insensitive to motion. This study evaluated the initial application of dual-energy subtraction in cardiac patients. The image quality of dual-energy subtraction left ventriculograms obtained from a pulmonary artery injection of contrast was assessed in 13 patients, ranging in weight from 54 to 100 kg. The dual-energy images were compared with left ventricular images obtained using standard left ventricular injection cine angiography. End-systolic and end-diastolic ventricular volumes calculated from the cine (C) and dual-energy (DE) images using the Area-Length method were compared. The resulting regression line was DE=0.98 C + 7.0 ml, and the r value was 0.987. Dual-energy subtraction provided good left ventricular visualization, free from misregistration artifacts, even during patient motion.

Effect of oral milrinone on end-systolic relations in patients with severe congestive heart failure

The new inotropic agent milrinone has both vasodilator and inotropic cardiovascular effects, but the importance of these effects in patients with severe congestive heart failure (CHF) is controversial. The left ventricular (LV) end-systolic pressure-diameter relation was used to determine the independent inotropic effect of milrinone. Seven patients with New York Heart Association class III CHF were invasively monitored with right-sided heart catheters and radial arterial lines. M-mode echocardiography was used to measure LV dimensions. The effect of a 10-mg oral dose of milrinone on hemodynamic, echocardiographic and end-systolic variables was determined. End-systolic pressure was measured at the dicrotic notch of the arterial pressure tracing and end-systolic LV dimensions at the time of aortic valve closure. Methoxamine (n = 6) or nitroprusside (n = 1) was used to alter afterload so that the end-systolic pressure-diameter relation could be determined. Arterial vasodilation from milrinone was evidenced by a decrease in mean arterial blood pressure (88 +/- 5 to 77 +/- 2 mm Hg, p less than 0.025) and an increase in cardiac index (from 2.7 +/- 0.2 to 3.2 +/- 0.2 liters/min/m2, p less than 0.025), with no change in heart rate (80 +/- 5 beats/min). Milrinone decreased preload as assessed by the pulmonary artery wedge pressure (from 17 +/- 2 to 10 +/- 2 mm Hg, p less than 0.01) and end-diastolic LV diameter (from 7.4 +/- 0.4 to 7.0 +/- 0.4 cm, p less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

Improved densitometric measurement of left ventricular ejection fraction using dual-energy digital subtraction angiography *

The effects of misregistration artifacts and background corrections on the densitometric measurement of left ventricular ejection fraction (EF) from digital subtraction angiography (DSA) images were studied in 20 patients. Densitometric ejection fraction measurements were performed on both conventional time subtraction images and on dual-energy subtraction images. Dual-energy subtraction is not sensitive to the motion induced artifacts which often mar time subtraction images. While the time subtraction images had varying degrees of misregistration artifacts, none of the dual-energy studies contained significant misregistration artifacts. Densitometrically determined ejection fractions measured with and without correction for background signals were compared. Poor agreement between time subtraction ejection fractions determined with and without background correction (EFNO-BKG=0.88 EFBKG −6.0%, SEE=8.1%, r=0.83) demonstrated the sensitivity of time subtraction EFs to the performance of a background correction procedure. Conversely, densitometric measurement of ejection fraction using dual-energy subtraction was significantly less sensitive to the performance of a background correction (EPNO-BKG=0.99 EFBKG −5.3%, SEE=4.3%, r=0.96). Since background correction requires accurate definition of ventricular borders, but motion artifacts often preclude accurate border definition, it is concluded that dual-energy subtraction is a significantly more robust method for measuring left ventricular ejection fraction using densitometry. It is further concluded that identification of the systolic endocardial border is not required when performing densitometric EF measurements on dual-energy images. Drawing of the end-diastolic border alone is sufficient to produce an accurate ejection fraction measurement.

Effect of altered contractility on the linearity of regional left ventricular end-systolic relations in intact hearts.

The purpose of these studies was to determine the effect of altered regional contractility on the linearity of regional left ventricular end-systolic relations. Significant change in the shape of these relations would limit their application as load-independent indices of regional contractility. In a paced, open-chest pig heart preparation (n = 7), the left ventricular end-systolic pressure-segment length relation (ESPLR) and pressure-wall thickness relation (ESPTR) were obtained over a wide range of end-systolic pressures (134 +/- 9 to 70 +/- 6 mm Hg). Regional inotropic state was varied with intracoronary calcium and verapamil. The shapes of the ESPLR and ESPTR were characterized by using linear and quadratic models. Both provided a good fit, although the quadratic model showed a slight concavity to the segment length and thickness axes (second-order coefficient < 0). In the linear model, calcium increased the slope of the ESPLR by 111% (p < 0.01) and the slope of the ESPTR by 170% (p < 0.01). At a pressure of 100 mm Hg, end-systolic segment length (L100) shifted to the left (p < 0.05) and end-systolic wall thickness (T100) to the right (p < 0.025). Verapamil decreased the slope of the ESPLR by 45% (p < 0.01) and of the ESPTR by 33% (p not significant) and produced significant shifts in L100 (p < 0.001) and T100 (p < 0.025). The values of L100 and T100 determined by the quadratic fit were nearly identical to those for the linear fit, and both showed similar significant shifts with altered contractility. There was no significant change in the shape of the quadratic fit (as assessed by the second-order coefficient) with different contractile states. It is concluded that the curvilinearity of the ESPLR and ESPTR under physiologic conditions is slight and appears to be independent of the contractile state. Furthermore, a linear model of regional end-systolic relations can be used to assess regional left ventricular function in intact hearts.

Densitometric assessment of regional left ventricular systolic function during graded ischemia in the dog by use of dual-energy digital subtraction ventriculography

Densitometric analysis of images obtained by digital subtraction angiography (DSA) allows for more reproducible and less operator-dependent quantitation of ventricular function. Conventional DSA uses temporal subtraction but is limited by misregistration artifacts. Dual-energy digital subtraction angiography (DE-DSA) is immune to such misregistration artifacts. The ability of DE-DSA to quantitate changes in regional ventricular volume resulting from ischemia was tested. Densitometric analysis of both phase-matched and ejection fraction DE-DSA images was used to quantitate regional left ventricular systolic function during four levels of ischemia ranging from mild to severe in open-chest dogs (n = 10). DE-DSA left ventriculograms were obtained by means of central venous injections of iodinated contrast medium. Ischemia was graded according to percentage of systolic wall thickening as measured by sonomicrometry. Phase-matched end-systolic images were obtained at each of four levels of ischemia by subtracting an end-systolic control image from each end-systolic ischemic image. Ejection fraction images were obtained at the control level and at each level of ischemia by subtracting an end-systolic image from an end-diastolic image of the same cardiac cycle. The resulting wall motion difference signals represent the changes in regional ventricular volumes and were quantitated by densitometry. Densitometry was able to detect the effect of all levels of ischemia on regional function, even the mildest. Densitometric analysis of both phase-matched and ejection fraction DE-DSA images provides a sensitive technique for detecting and quantitating the changes in regional left ventricular systolic volume that occur with ischemia.

Limitations of the End-Systolic Pressure-Diameter Relationship in Patients with Severe Congestive Heart Failure

The purpose of this study was to evaluate the usefulness of the end-systolic pressure-volume relationship, the end-systolic pressure-dimension relationship and the end-systolic wall stress-mean rate corrected velocity of circumferential fiber shortening relationship in patients with severe congestive heart failure due to a dilated cardiomyopathy

Delayed complete heart block complicating percutaneous transluminal coronary angioplasty

reducing ventricular distension. During regional ischemia in animal models, the Hemopump increases collateral perfusion within the risk region.6 Thus the Hemopump may be especially useful during transient ischemic episodes complicating high-risk coronary angioplasty. Although the Hemopump has a large 21F profile seated across the aortic valve, it did not interfere with routine coronary angiography or angioplasty. The Hemopump produces little hemolysis or aortic valve trauma, and thus may be useful for long-term support.6 Nevertheless, the size of the device and the requirement for placement via surgical arteriotomy of the femoral artery limit the speed of insertion. Furthermore, placement of the distal catheter in the left ventricular cavity can mechanically induce ventricular arrhythmias or dislodge mural thrombus. These preliminary findings suggest that circulatory assistance using the Nimbus Hemopump may be useful in high-risk patients undergoing coronary angioplasty. The long-term effect of this device on survival in patients with cardiogenic shock is currently under study.