In this study we introduce a new concept of systolic myocardial stiffness that extends the Suga-Sagawa maximum ventricular elastance concept to the myocardium. End-systole is defined as the time of maximum systolic myocardial stiffness (max Eav), which we examined for its load independence and sensitivity to changes in the inotropic state and to heart rate. Seven adult mongrel dogs were instrumented with ultrasonic crystals for measurements of long and short axes and left ventricular wall thickness, and a high-fidelity micromanometer was inserted for measurement of left ventricular pressures. Preload and afterload were altered by inferior vena cava occlusion, nitroprusside, angiotensin II, atropine, propranolol, and various combinations with propranolol. End-systolic stressstrain relations (slope: max Eav) were linear in all seven dogs, implying that end-systolic myocardial stiffness is independent of end-systolic stress. Changes in max Eav (for constant preload and afterload) reflected changes in the ejection fraction; max Eav was also insensitive to propranolol and to changes in heart rate over the range from 120 to 180 beats/min. End-systolic pressure-volume relations (ESPVRs), derived analytically from these stress-strain relations, were nonlinear, and estimates of volume at zero stress (Vom) [343][344][345][346][347][348][349][350][351][352][353][354][355][356] 1987. THE END-SYSTOLIC ventricular pressure-volume concept developed by Suga and Sagawal continues to be a subject of great interest and controversy. Many of these controversies have been addressed in several review articles2-5 and in recent American Heart Association abstracts (1984, 1985, 1986

We examined the effects of a cardioselective beta-blocking drug on exercise-induced regional myocardial ischemia in 10 conscious dogs with chronic coronary artery stenosis. An ameroid constrictor, Doppler flowprobe, and hydraulic cuff were placed around the left circumflex coronary artery, and left ventricular pressure (LVP), systolic wall thickening (% delta WT; by sonomicrometry), and myocardial blood flow (MBF; microspheres) were measured during control standing, control treadmill exercise, and identical exercise after atenolol (1 mg/kg po). Prior to study, in every dog % delta WT and MBF in the ischemic area were normal at rest, indicating collateral development. During control exercise, % delta WT in the ischemic region markedly decreased from 27 to 4%, and transmural ischemia was evident in that region. Heart rate, systolic LVP, and LV (+)dP/dt were significantly lower during exercise after atenolol than during control exercise. % delta WT in the normal area was only 81% of that during control exercise, but dysfunction in the ischemic area was improved (77% increase compared with control exercise). Accompanying the improved function was a significant increase of MBF/beat and relative MBF in the ischemic zone; the endocardial-to-epicardial ratio increased from 0.27 to 0.47. Thus atenolol improved regional MBF distribution, thereby diminishing exercise-induced regional myocardial dysfunction and accelerating its recovery.

No. 4, 801-814, 1984. THE CALCIUM-ENTRY BLOCKER diltiazem was developed as a drug that inhibits the influx of calcium ions during cell depolarization in vascular smooth muscle, thereby producing coronary vasodilation.1A Several studies have documented the beneficial effect of diltiazem in controlling symptoms of coronary artery spasm5-' and effort angina pectoris. '2 Diltiazem is also effective in increasing the total duration of exercise and the time to the first onset of angina, and the pressure-rate product is significantly reduced at sub-

Diastolic flow into the left ventricle during mitral regurgitation must increase as total stroke volume increases in response to the volume overload. The mechanisms that allow augmented diastolic filling are not fully defined. Accordingly, the left ventricle of five dogs was instrumented with a micromanometer and sonomicrometers and studied during the conscious state before (control) and after the creation of significant mitral regurgitation. Serial measurements were made at control and up to 4 weeks after the creation of the volume overload. Heart rate, peak systolic wall stress, and peak positive dP/dt showed no significant changes between control and subsequent observations. End-diastolic volume and total stroke volume progressively and significantly increased during the 4-week course. When compared with the control state (51 4, mean+± SD), the filling fraction during the first 40% of diastolic time was increased at 4 days (67±10%, p<0.001), 2 weeks (72±6%, p<0.001), and 4 weeks (76±10%, p<0.001). During the period of adaptation to the volume overload, filling fraction correlated with end-diastolic volume (r=0.52, p<0.02) and total stroke volume (r=0.80, p<0.001). Compared with the control state (0.81 + 0.04), eccentricity of the left ventricle at end systole decreased at 4 weeks (0.79 0.06, p<0.05); the absolute change in this ratio during the first 40% of diastolic time was significantly augmented at 2 weeks (0.09 ±+0.02, p<0.05) and 4 weeks (0.11 + 0.04, p<0.005) compared with control (0.05 0.02). Ventricular elastance (pressure/volume) at end systole (minimum volume) was 1.70+±0.50 mm Hg/ml at control, 1.09+± 0.46 at 4 days (p<0.05), 0.96±+0.42 at 2 weeks (p<0.01), and 0.99 0.22 at 4 weeks (p<0.01). Moreover, the elastance change during the rapid-filling phase was significantly diminished after creation of mitral regurgitation. Thus, during the volume overload of mitral regurgitation, the left ventricle accommodates a higher percentage of its total stroke volume during early diastole; this adaptation can be correlated with augmented systolic shortening, and thereby with increased restorative forces or elastic recoil, and with reduced chamber elastance and eccentricity during the early part of diastole. Other potential mechanisms include altered systolic and relaxation loading, augmented elastic recoil of the left atrium, left atrium and left ventricular pressure gradient, accelerated myocardial inactivation, and increased adrenergic stimulation. (Circulation 1988; 78:390-400) L eft ventricular volume overload has undergone extensive experimental investigation, and a number of adaptive mechanisms, including increased sarcomere stretch (Frank-Starling pnnciple), 1-3 hypertrophy,4,5 variable changes in inotropism,6-9 decreased operational end-diastolic compliance,10 and altered coronary vasodilator

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