Kenneth M. Borow

Left ventricular end-systolic wall stress-velocity of fiber shortening relation : A load-independent index of myocardial contractility

The velocity of circumferential fiber shortening (Vcf) is an index of myocardial performance which, although sensitive to contractile state, has limited usefulness because of its dependence on left ventricular loading conditions. This study investigated the degree and velocity of left ventricular fiber shortening as it relates to wall stress in an attempt to develop an index of contractility that is independent of preload and heart rate while incorporating afterload. Studies were performed in 78 normal subjects using M-mode echocardiography, phonocardiography and indirect carotid pulse tracings under baseline conditions. In addition, studies were performed on 25 subjects during afterload augmentation with methoxamine, 8 subjects before and during afterload challenge after increased preload with dextran and 7 subjects with enhanced left ventricular contractility with dobutamine. The relation of end-systolic stress to the velocity of fiber shortening and to the rate-corrected velocity of shortening (corrected by normalization to an RR interval of 1) was inversely linear with correlation coefficients of -0.72 and -0.84, respectively. Alterations in afterload, preload or a combination of the two did not significantly affect the end-systolic wall stress/rate-corrected velocity of shortening relation, whereas during inotropic stimulation, the values were higher, with 94% of the data points above the normal range. Age did not appear to affect the range of normal values for this index. In contrast, the end-systolic wall stress/fractional shortening relation was not independent of preload status, responding in a manner similar to that seen with a positive inotropic intervention. Thus, the velocity of circumferential fiber shortening normalized for heart rate is inversely related to end-systolic wall stress in a linear fashion. Accurate quantitation can be performed by noninvasive means and a range of normal values determined. This index is a sensitive measure of contractile state that is independent of preload, normalized for heart rate and incorporates afterload. In contrast, the end-systolic wall stress/fractional shortening relation is dependent on end-diastolic fiber length in the range of physiologically relevant changes in preload.

End-systolic volume as a predictor of postoperative left ventricular performance in volume overload from valvular regurgitation.

Abstract Although over-all cardiac performance may remain normal in patients with left ventricular volume overload from valvular regurgitation, impairment of myocardial function may occur and remain undetected by currently accepted methods of assessing ventricular performance. Since end-systolic volume reflects myocardial contractile function yet is independent of preload, we assessed preoperative end-systolic volume as a measure of myocardial function in 41 patients with aortic regurgitation, mitral regurgitation or both. Preoperative end-systolic volume was compared to postoperative left ventricular performance as measured by postoperative echocardiographic per cent dimension change (% ΔD) and New York Heart Association class. Preoperative end-systolic volume correlated well with postoperative left ventricular performance in patients with aortic regurgitation (r = 0.77) or mitral regurgitation (r = 0.73). Much poorer correlations existed for preoperative ejection fraction, enddiastolic volume or left ventricular end-diastolic pressure. Preoperative end-systolic volume also predicted patients at high risk for perioperative cardiac death, with all such cardiac deaths occurring in patients with an end-systolic volume >60 cc/m 2 . Again, both preoperative ejection fraction and end-diastolic volume were less precise predictors of surgical outcome. Patients with aortic regurgitation appeared to tolerate a larger end-systolic volume better than those with mitral regurgitation. End-systolic volume is an easily determinable parameter of left ventricular function which is independent of the abnormal preload that occurs in mitral regurgitation and aortic regurgitation and appears to provide a measure for the onset of myocardial dysfunction in patients with these lesions. Whether this myocardial dysfunction is due to a depressed inotropic state of individual sarcomeres, a stress-shortening imbalance or to other factors is unknown, but its presence has major prognostic importance.

Left ventricular end-systolic stress-shortening and stress-length relations in humans

Abstract Experimental studies suggest that the extent of left ventricular (LV) fiber shortening is determined by both the wall stress at end-systole and the contractile state. To evaluate the relation between these variables assessed noninvasively, 26 normal subjects were studied by M-mode echocardiography, phonocardiography, and indirect carotid pulse tracings during infusion of methoxamine to alter load (in all 26 subjects) and infusion of dobutamine (in 10 subjects) to increase contractility. End-systolic pressure was estimated from the incisura of a calibrated carotid pulse tracing. LV end-systolic dimension and wall thickness, and percent internal dimension shortening were determined by echocardiography, and end-systolic meridional wall stress was calculated. The relation between end-systolic stress and shortening was inversely linear (r = −0.83) for 130 control points. Dobutamine infusion resulted in a higher percent fractional shortening for any end-systolic stress; all 43 stress-shortening points were more than 2 standard deviations above the mean for the regression line. The relation between stress and dimension for the control points showed wider scatter than between stress and shortening (r = 0.56). However, in individual patients dobutamine always shifted the stress-dimension lines to the right, as compared with the baseline position resulting in a smaller end-systolic dimension for any end-systolic wall stress. Thus, LV end-systolic wall stress and percent fractional shortening are inversely and linearly related and their relation can be accurately assessed by noninvasive methods. The end-systolic stress-shortening relation is highly sensitive, while the end-systolic stress-dimension relation is less sensitive to alterations in LV inotropic state.

Sensitivity of end-systolic pressure-dimension and pressure-volume relations to the inotropic state in humans.

The value for the slope of the left ventricular (LV) end-systolic pressure-dimension and pressure-volume relations has been proposed as a quantitative measure of the LV inotropic state. This measure of LV inotropic state is attractive because it is independent of preload and incorporates afterload. To investigate the sensitivity of the slope of these relations to alterations in contractile state, 10 normal subjects were studied using M-mode echocardiographic, phonocardiographic and indirect carotid pulse recordings during infusion of methoxamine to alter end-systolic pressure and during infusion of dobutamine (5 ug/kg/min) to increase LV inotropic state. Heart rate was maintained within a narrow range for each subject. End-systolic volume was calculated from end-systolic echocardiographic dimension by standard methods. End-systolic pressure was estimated from the dicrotic notch pressure determined from a calibrated carotid pulse recording; peak systolic pressure was also measured. Regardless of the method of approximating end-systolic pressure, the positive inotropic intervention caused a leftward shift in the end-systolic pressure-dimension and pressurevolume lines. With the dobutamine infusion, the value for the slope of the end-systolic pressure-dimension relation increased by 25% (range 16-46%, p < 0.001), while the slope of the end-systolic pressure-volume relation increased by 55% (range 37-85%, p < 0.001). In all cases, the curves were linear and became steeper with the positive inotropic intervention. In contrast, the value of the slope of the peak systolic pressure-end-systolic dimension relation showed a variable response to the dobutamine infusion (mean change 13%, range -77% to 73%; NS). Although the position of the peak systolic pressure-end-systolic dimension curve is consistently shifted with an alteration in inotropic state, the values of the slope of these curves are not reliable indicators of change in LV contractility. The values for the slope of the line relating end-systolic pressure (estimated by dicrotic notch pressure) to end-systolic dimension or volume, however, are highly sensitive to a change in inotropic state in human subjects.

Left Ventricular Contractility Varies Directly with Blood Ionized Calcium

STUDY OBJECTIVE To determine the effect of variations in blood ionized calcium (Ca2+) on myocardial contractility independent of changes in loading conditions and other biochemical variables. DESIGN Hemodialysis done in a randomized, double-blind manner with dialysates differing in calcium concentration only. Left ventricular contractility was assessed using the load- and heart rate-independent relationship between end-systolic wall stress (sigma es) and rate-corrected velocity of fiber shortening (Vcfc). SETTING In-hospital dialysis unit and echocardiography laboratory of a university medical center. PATIENTS Seven patients with stable, chronic renal failure maintained on regular hemodialysis. INTERVENTIONS Each patient was hemodialyzed three times within 1 week with dialysates differing in calcium concentration only. Ultrafiltration was adjusted to achieve the same postdialysis weight. Immediately after dialysis, two-dimensionally targeted M-mode echocardiographic and calibrated carotid pulse tracings were recorded over a wide range of left ventricular end-systolic wall stress values (a measure of left ventricular afterload) generated by either methoxamine or nitroprusside. MEASUREMENTS AND MAIN RESULTS After dialysis, three statistically distinct levels of Ca2+ were achieved. When Ca2+ was 1.34 +/- 0.03 mmol/L, Vcfc, calculated at a common level of afterload (sigma es = 50 g/cm2), was 1.01 +/- 0.05 cir/sec; at low Ca2+ (1.02 +/- 0.02 mmol/L), Vcfc fell to 0.89 +/- 0.04 cir/sec (P less than 0.001 compared with medium); at high Ca2+ (1.68 +/- 0.07 mmol/L) Vcfc rose to 1.10 +/- 0.03 circ/sec (P less than 0.001 compared with medium and low). CONCLUSION Variations in Ca2+ are directly correlated with clinically significant changes in myocardial contractility.

Systemic vascular resistance: an unreliable index of left ventricular afterload

Systemic vascular resistance (SVR) is a frequently used clinical index of left ventricular afterload. However, SVR may not adequately assess left ventricular afterload (i.e., ventricular internal fiber load during systole) since it reflects only peripheral vasomotor tone. In contrast, left ventricular end-systolic wall stress (sigma es) reflects the combined effects of peripheral loading conditions and left ventricular chamber pressure, dimension, and wall thickness. To determine the relationship between SVR and sigma es, left ventricular afterload and contractility were pharmacologically altered in eight dogs instrumented with central aortic microtip and Swan-Ganz thermodilution catheters. Left ventricular wall thicknesses and dimensions were measured from two-dimensionally targeted M mode echocardiograms. Aortic, right atrial, and left ventricular end-systolic pressures as well as cardiac output were recorded. SVR and sigma es were determined under control conditions as well as during infusions of nitroprusside, methoxamine, dobutamine, and norepinephrine. Control data acquired before each drug infusion were similar. When compared with baseline values, SVR underestimated the magnitude of change in left ventricular sigma es by 22% when afterload alone was decreased (nitroprusside), 54% when afterload alone was increased (methoxamine), and 50% when afterload was decreased and contractility was augmented (dobutamine). Most importantly, when afterload was minimally decreased in association with augmented contractility (norepinephrine), SVR increased by 21% while sigma es fell by 9%. Thus, discordant changes in left ventricular afterload (i.e., sigma es) and SVR can occur during pharmacologic interventions. SVR is an unreliable index of left ventricular afterload, reflecting only peripheral arteriolar tone rather than left ventricular systolic wall force. This emphasizes the fact that a true measure of left ventricular afterload must consider the interaction of factors internal and external to the myocardium.

Left ventricular diastolic function in elite athletes with physiologic cardiac hypertrophy

Left ventricular hypertrophy due to aortic stenosis, hypertension and other forms of heart disease is associated with abnormalities of diastolic function. It is uncertain whether these changes are an inherent consequence of the hypertrophic process or represent additional pathologic factors. To investigate this issue, echocardiographic indexes of left ventricular early diastolic function in highly trained athletes were compared with those in age-matched normal control subjects. Athletes were equally classified into two groups: 11 swimmers who had a pattern of myocardial hypertrophy with normal wall thickness to dimension ratio and 11 power lifters whose wall thickness to dimension ratio was increased. The peak rates of left ventricular dimension increase and wall thinning in swimmers and power lifters were greater than in control subjects despite significantly higher left ventricular wall thickness and left ventricular mass index in the athletes. This increase in diastolic function indexes was associated with greater ventricular size and systolic performance. Normalization of the peak rate of dimension increase for end-diastolic dimension and adjustment of the peak rate of wall thinning for the fractional systolic thickening resolved any differences between groups. Thus, after the effects of ventricular size and systolic function were taken into consideration, diastolic function was normal in these subjects with considerable physiologic hypertrophy. This is in contrast to the findings in patients with hypertrophy associated with left ventricular pressure or volume overload, and suggests that abnormalities of diastolic function seen in pathologic hypertrophy are due to factors other than cardiac hypertrophy itself.

The differential effects of positive inotropic and vasodilator therapy on diastolic properties in patients with congestive cardiomyopathy.

Symptoms of congestive heart failure frequently reflect abnormalities in both systolic and diastolic performance. While much work has been reported regarding the mechanisms by which positive inotropic and vasodilator therapy affect systolic performance, little is known about their effect on diastolic function. In 12 patients with diffuse congestive cardiomyopathy micromanometer left ventricular and aortic pressure measurements were recorded simultaneously with two-dimensionally targeted M mode echocardiograms and thermodilution-determined cardiac output. Each patient received dopamine (2, 4, and 6 micrograms/kg/min), and dobutamine (2, 6, and 10 micrograms/kg/min), and 10 received nitroprusside (0.125 to 2.0 micrograms/kg/min). Baseline hemodynamics were characterized by low cardiac index (2.1 +/- 0.7 liter/min/m2, mean +/- SD), high left ventricular end-diastolic pressure (24 +/- 10 mm Hg), and increased end-diastolic (6.8 +/- 1.0 cm) and end-systolic dimensions (6.0 +/- 1.0 cm). All patients had abnormal left ventricular pressure decay with a prolonged time constant (67 +/- 20 msec) and reduced peak diastolic lengthening rates. Dopamine and dobutamine decreased the time constant of relaxation and increased the peak lengthening rate. Dobutamine also reduced the minimum diastolic pressure from 14 +/- 7 to 10 +/- 9 mm Hg (p less than .01); neither drug reduced end-diastolic pressure. In fact, dopamine elevated end-diastolic pressures in seven patients, despite more rapid pressure decay. Diastolic pressure-dimension relations after dopamine and dobutamine showed a leftward shift with a reduced end-systolic chamber size, but no significant changes in passive chamber stiffness. Nitroprusside decreased left ventricular minimum diastolic pressure by 4 +/- 2 mm Hg and end-diastolic pressure by 7 +/- 4 mm Hg (p less than .01). It did not consistently accelerate left ventricular pressure decay at the doses tested. The decreased end-diastolic pressure with nitroprusside was due to a reduced end-diastolic dimension in five patients. In the other patients, all of whom had elevated right atrial pressures, diastolic pressure-dimension relations showed a parallel downward shift after nitroprusside. Thus, positive inotropic therapy with beta 1-adrenoceptor agonists enhances early diastolic distensibility by accelerating relaxation, augmenting filling, and reducing end-systolic chamber size. Vasodilator therapy is much more effective in lowering diastolic pressures.(ABSTRACT TRUNCATED AT 400 WORDS)

PHYSIOLOGIC HYPERTROPHY: EFFECTS ON LEFT VENTRICULAR SYSTOLIC MECHANICS IN ATHLETES

Physiologic hypertrophy resulting from intense athletic participation has been reported to result in normal, reduced and augmented overall left ventricular performance. Rather than representing true differences in left ventricular contractility, these data may reflect the variable degree of ventricular dilation and increased wall thickness that occur with different types of exercise. As such, the resultant altered loading conditions may diminish the ability of the usual indexes of left ventricular function to accurately assess the left ventricular contractile state. Therefore, three groups of elite athletes with distinct patterns of myocardial hypertrophy were investigated utilizing recently developed load-independent contractility indexes. Age-matched control subjects (n = 33) were compared with 11 swimmers, 11 long-distance runners and 11 power lifters. Rest echocardiogram, phonocardiogram and calibrated carotid pulse tracing were used to calculate left ventricular dimensions, wall thickness, mass, fractional shortening, velocity of shortening and mean, peak and end-systolic wall stresses and the stress-time and minute stress-time integrals. Compared with control subjects, all athletes had increased left ventricular mass, even when values were normalized for body surface area. Runners had a dilated left ventricular and normal wall thickness, swimmers had a mildly dilated ventricle with increased wall thickness and power lifters had normal cavity size with markedly increased wall thickness. Peak systolic wall stress was normal in runners and swimmers and reduced in power lifters, whereas end-systolic stress was low in swimmers and power lifters and normal in runners. The minute stress-time integral, a measure of myocardial oxygen consumption, was normal in runners and swimmers but was significantly reduced in lifters.(ABSTRACT TRUNCATED AT 250 WORDS)

Congestive heart failure due to adriamycin cardiotoxicity: its natural history in children.

The congestive heart failure (CHF) associated with Adriamycin cardiotoxicity is frequently fatal. To investigate the course of Adriamycin‐induced congestive heart failure, all Adriamycin‐treated children who developed congestive heart failure at the Childrens Hospital Medical Center and Sidney Farber Cancer Institute were studied. Criteria for Adriamycin‐induced congestive heart failure included clinical evidence of left ventricular (LV) failure and echocardiographic evidence of abnormal left ventricular function. Fifteen children fulfilled these criteria. Eleven patients received between 400 and 500 mg/m2 of Adriamycin; four patients received cumulative doses over 500 mg/m2. Twelve of 15 (80%) children survived their acute episode of congestive heart failure. At follow‐up, three patients had normalized their echocardiographic parameters of left ventricular function, three had died of their malignancies with compensated cardiac function until death, and six were clinically asymptomatic despite persistence of abnormal LV function on echocardiogram. Only three patients died of Adriamycin cardiomyopathy. In children treated with aggressive medical therapy, congestive heart failure secondary to Adriamycin cardiotoxicity may be reversible in certain cases.