James F. Spann

Differences in myocardial performance and load between patients with similar amounts of chronic aortic versus chronic mitral regurgitation

It is not known if the favorable changes in preload and afterload that augment ejection performance in acute experimental aortic and mitral regurgitation are also present in patients with chronic regurgitation. Additionally, observations that patients with mitral versus aortic regurgitation respond differently to valve replacement suggest that differences exist preoperatively between these two types of volume overload. Therefore, ventricular mechanics were compared in nine patients with severe aortic regurgitation, eight patients with severe mitral regurgitation and seven normal subjects. The amount of volume overload was similar in both groups with regurgitation. In both aortic and mitral regurgitation, ejection performance was reduced compared with findings in normal subjects. Preload estimated as enddiastolic stress was comparably elevated above normal in both groups with regurgitation: 69 +/- 24 dynes X 10(3)/cm2 in mitral regurgitation compared with 81 +/- 34 dynes X 10(3)/cm2 in aortic regurgitation and 36 +/- 11 dynes X 10(3)/cm2 in normal subjects. However, afterload estimated as mean systolic stress was normal in mitral regurgitation (186 +/- 34 dynes X 10(3)/cm2) but markedly elevated in aortic regurgitation (260 +/- 41 dynes X 10(3)/cm2) (p less than 0.01). Contractile depression tended to be more severe in mitral regurgitation despite similar ejection performance in mitral and aortic regurgitation. Thus, in mitral regurgitation favorable loading conditions may mask contractile dysfunction, and in aortic regurgitation excessive afterload contributes to poor pump performance, possibly accounting for previously observed differences in the response to valve replacement.

Coronary thrombolysis by intravenous streptokinase in acute myocardial infarction: Acute and follow-up studies

Coronary arteriography was performed before, immediately after, and 9 to 14 days after administering i.v. streptokinase (850,000 to 1,500,000 IU) to 43 patients within 6 hours of myocardial infarction. Ventricular function was determined by contrast ventriculography before and 9 to 14 days later and by radionuclide studies at clinical follow-up 8 months later. Early reperfusion occurred in 49% of patients, but in only 35% was it sustained. In patients with sustained reperfusion, early ventricular dysfunction was significantly reduced 9 to 14 days and 10 months later, and frequency of infarction, sudden death, and angina pectoris was not increased at follow-up. No serious bleeding occurred.

Cardiac function in sickle cell anemia

Although ventricular dysfunction is suspected to underlie congestive heart failure in sickle cell anemia (SCA), ejection indexes of left ventricular (LV) pump performance have been found to be normal. The increased preload and decreased afterload of SCA increases the ejection phase indexes and might obscure true LV dysfunction. Therefore, the preload and afterload independent end-systolic stress-volume index was compared in 11 patients with SCA and in 11 normal volunteers. End-systolic pressure and echocardiographic LV dimensions were determined during rest, leg raise, hand-grip and amyl nitrite inhalation. Systemic vascular resistance (afterload) was decreased to 1,033 +/- 314 dynes s cm-5 (mean +/- standard deviation) in SCA from 1,701 +/- 314 dynes s cm-5 in normal subjects. End-diastolic volume index (preload) was increased to 102 +/- 24 ml/m2 in SCA from 66 +/- 10 ml/m2 in normal subjects. Cardiac index was increased to 4.7 +/- 1.1 liters/min/m2 in SCA from 2.8 +/- 0.8 liters/min/m2 in normal subjects. Ejection fractions were similar: 0.59 +/- 0.09 in SCA versus 0.62 +/- 0.07 in normal subjects. However, in patients with SCA, the ratio of resting end-systolic stress-volume index was decreased (1.5 +/- 0.5 in SCA versus 2.8 +/- 0.6 in normal subjects) and the slope of the end-systolic stress versus end-systolic volume index relation was decreased (2.7 +/- 1.3 in SCA versus 4.4 +/- 1.8 in normal subjects), suggesting LV dysfunction in those patients. Thus, LV muscle contractile performance is depressed in SCA. Increased preload and decreased afterload compensate for the LV dysfunction and maintain a normal ejection fraction and high cardiac output.

Left ventricular function in chronic aortic regurgitation with reference to end-systolic pressure, volume and stress relations☆

Left ventricular muscle and pump performance were evaluated in 12 normal subjects and 21 patients with aortic regurgitation (10 with minimal symptoms and 11 with congestive heart failure). A computer-based quantitative analysis of biplane left ventriculograms was used. Both patient groups had significant aortic regurgitation documented by ventriculography. Contractile function measured by peak systolic stress/end-diastolic volume and end-systolic pressure/volume curves was poorer than that in normal subjects in patients with heart failure but not in asymptomatic patients. When normalized for muscle mass, stroke work was not depressed in either asymptomatic patients (mean +/- standard error of the mean 0.008 +/- 0.001 joules/g) or patients with heart failure (0.009 +/- 0.004) by comparison with the value in normal subjects (0.010 +/- 0.001). Angiographically determined cardiac index (CI) increased with increasing volume overload even though forward cardiac index measured by the Fick method remained essentially unchanged: normal subjects (total CI 3.7 +/- 0.4 liters/min per m2, Fick CI 2.4 +/- 0.1); asymptomatic patients (total CI 7.6 +/- 0.7, Fick CI 2.3 +/- 0.2); patients with heart failure (total CI 9.1 +/- 0.82, Fick CI 2.1 +/- 0.18). Left ventricular peak stress increased significantly in patients with heart failure (511 +/- 55 dynes/cm2 x 10(-3)) compared with values in normal subjects (360 +/- 33) and asymptomatic patients (428 +/- 50). The combination of decreased muscle function and increased demands on pump function causes a significant increase in end-diastolic pressure only in patients with heart failure (23 +/- 2 mm Hg), which results in pulmonary congestive symptoms.

High-dose, brief intravenous streptokinase early in acute myocardial infarction☆

An acute thrombus at the proximal border of a high-grade atherosclerotic obstruction is the usual cause of myocardial infarction. Although intracoronary thrombolysis is potentially an exciting new therapy for reducing the extent of myocardial infarction by lysing coronary clot, a number of major difficulties limit its widespread application. It is a complex procedure requiring intracoronary visualization and infusion within a few hours of onset of symptoms. Since intravenous streptokinase could be widely applied if effective, we and others have wondered whether high-dose, brief-duration intravenous streptokinase infusion given early in myocardial infarction would lyse coronary clots without bleeding. To date we have treated 13 patients within 6 hours of onset of symptoms and with ECG and angiographic evidence of typical myocardial infarction caused by coronary clot. Clot lysis and angiographically proved coronary reperfusion were achieved in 6 patients within 1 hour of starting a systemic intravenous infusion of 850,000 IU of streptokinase. Schroeder et al., in Berlin, West Germany, achieved angiographically proved coronary reperfusion in 11 of 21 patients with acute myocardial infarction following a 30-minute intravenous streptokinase infusion of 500,000 IU. Neuhaus et al., in Göttinen, West Germany, achieved angiographically proved coronary reperfusion in 24 of 39 similar patients within 48 minutes by intravenous infusion of 1,700,000 IU of streptokinase. In these three studies, no serious bleeding occured; left ventricular function was improved in patients who achieved coronary reperfusion. We conclude that rapid intracoronary clot lysis and coronary reperfusion can be achieved early in myocardial infarction by brief-duration systemic intravenous infusion of high-dose streptokinase without a high incidence of serious bleeding.

Coronary Thrombolysis for Evolving Myocardial Infarction

SummaryAn acute thrombus at the site of an atherosclerotic obstruction is the usual cause of myocardial infarction. Thrombolytic therapy is an exciting new therapy for reducing the extent of myocardial infarction by lysing intracoronary clots. Such therapy has now been widely applied by: prolonged intravenous infusion of streptokinase during the first 24 hours of infarction; intracoronary infusion of streptokinase, urokinase, or tissue plasminogen activator; early, high dose, brief duration intravenous infusion of streptokinase; or intravenous infusion of tissue plasminogen activator.Intracoronary streptokinase or urokinase achieves reperfusion of the coronary artery in 75% of patients and is associated with serious bleeding in 4.8% of patients. Intravenous infusion of streptokinase achieves reperfusion of the coronary artery in 50 to 80% of patients. The incidence of serious bleeding with intravenous streptokinase averaged 0.8% in 5 studies of 237 patients and was 12.8% in I additional study of 80 patients. Salvage of the jeopardised myocardium and improvement in left ventricular function occurred when coronary reperfusion was achieved. Mortality in streptokinase-treated patients was significantly reduced at 30 days and at 6 months after infarction in the single randomised mortality study done to date; however, more data are needed on this important question. Reocclusion after thrombolysis averages 17% in patients treated with streptokinase by either intracoronary or intravenous infusion.The newly reperfused coronary artery has been stabilised in some patients by coronary bypass surgery or percutaneous transluminal angioplasty, but further studies are needed to define criteria for appropriate patient selection for these procedures.

Blood collection techniques, heparin and quinidine protein binding.

With the use of glass syringes without heparin and all glass equipment, the percent of unbound quinidine was measured by ultrafiltration and a double‐extraction assay method after addition of 2 µg/ml of quinidine sulfate. Compared to the all‐glass method, collection of blood using Vacutainers resulted in an erroneous and variable decrease in quinidine binding related to blood to rubber‐stopper contact. With glass, the unbound quinidine fraction was (mean ± standard error) 10 ± 1% in 10 normal volunteers, 8.5 ± 1.5% in 10 patients with congestive heart failure, and 11 ± 2% in 11 patients with chronic renal failure (although in 8 of the latter 11 patients the percent of unbound quinidine was 4 or more standard errors from the mean of the normal group). During cardiac catheterization, patients had markedly elevated unbound quinidine fractions: 24 ± 2% (p < 0.001). This abnormality coincided with the addition of heparin in vivo and was less apparent after the addition of up to 10 U/ml of heparin in vitro (120% and 29% increase in unbound quinidine fractions, respectively). Quinidine binding should be measured with all glass or equivalent equipment.

Computer analysis of left ventricular dynamic geometry in man

Analysis of left ventricular performance in 20 normal patients was undertaken using biplane cineangiography and a semiautomatic computer image processing system. The analysis included evaluation of volumes, ejection fraction, regional shortening, patterns of ejection and filling and, when simultaneous left ventricular pressure was recorded stroke work, stroke power, wall stress and internal myocardial work. All of these data were calculated from digitized images stored permanently on digital magnetic tape, and can be reproduced without reanalysis of the cine film. Normal left ventricular function is described by an end-diastolic volume index of 82 +/- 3 ml, an ejection fraction of 60 +/- 2 percent, left ventricular mass index of 97 +/- 6 g/m2, peak first derivative of volume (dV/dt) of 485 +/- 28 ml/sec, anterior shortening of 48 +/- 2.3 percent, inferior shortening of 33 +/- 1.7 percent, lateral shortening of 29 +/- 1.5 percent, anterior mean shortening velocity (Vcf, in percent of end-diastolic length [L]/sec) of 1.5 +/- 0.1 L/sec, inferior Vcf of 1.1 +/- 0.06 L/sec and lateral Vcf of 0.94 +/- 0.2 L/sec, stroke work of 1.33 +/- 0.21 joules, mean stroke power of 3.7 +/- 0.62 joules/sec, integrated left ventricular pressure (tension-time index) of 2,866 +/- 340 mm Hg-sec, and integrated stress (stress-time index) of 7,260 +/- 765 (X 10(3)) dynes sec/cm2. Internal myocardial work was calculated from the strain energy. More internal work was expended in circumferential than logitudinal shortening (circumferential, 0.69 +/- 0.1 joules; longitudinal, 0.41 +/- 0.08, P less than 0.01), because hoop stress was greater than meridian stress (hoop, 201 +/- 20 dynes/cm3 X 10(3); meridian, 126 +/- 13, P less than 0.001). This analysis of left ventricular performance provides a reliable means for identifying abnormal ventricular function and may be more sensitive than any one measurement alone. The use of digital image processing makes this complex functional analysis of left ventricular performance feasible.

Quinidine pharmacokinetics in patients with cirrhosis or receiving propranolol

Quinidine pharmacokinetics (half-life, volume of distribution, and clearance) as well as protein binding were evaluated following a single 200 mg. oral dose of quinidine sulfate in eight control patients, in eight patients with moderate to severe cirrhosis, and in seven patients receiving 40 to 400 mg./day of propranolol. Patients with cirrhosis had a significantly longer quinidine half-life (9 +/- 1 hr; p less than .01) when compared to control patients (6 +/- 0.5h). This was not related to a reduced quinidine clearance rate but rather to an increase in quinidine volume of distribution (4.1 +/- .4 L./Kg. in cirrhotic patients vs 2.6 +/- 1 L./Kg. in control patients; p less than .01). Abnormal quinidine binding (greater than 25 per cent unbound fraction) was noted in seven of the eight cirrhotic patients. In contrast, patients receiving propranolol had a normal quinidine half-life of 6 +/- 0.5 hr. However, these patients had a significantly reduced quinidine clearance (3.3 +/- .7 ml./min./Kg. vs. 5.3 +/- .5 ml./min./Kg. in controls; p less than .05) and higher peak concentrations (1.25 +/- .20 micrograms/ml. vs. .80 +/- .5 micrograms/ml. in controls; p less than .05). Therefore in patients receiving propranolol, quinidine levels may be higher than expected shortly after dosage, and therefore a potential for transient toxicity exists in these patients. Maintenance quinidine dosage may have to be reduced in patients with moderate to severe hepatic cirrhosis, but not in patients receiving propranolol. Total quinidine concentration measurement underestimate free quinidine concentrations in most cirrhotic patients.

Right ventricular performance in mitral stenosis

Until recently, the dynamic geometry and pump function of the pressure-overloaded right ventricle in patients with mitral stenosis and pulmonary hypertension had not been well defined. With use of a recently developed method for calculating right ventricular volume in human beings, seven normal subjects and eight patients with mitral stenosis and pulmonary hypertension had right ventricular performance assessed from computer-analyzed biplane right ventriculograms. Patients with mitral stenosis has elevated values for systolic right ventricular pressure (mean +/- standard error of the mean 25 +/- 2 for normal subjects, 57 +/- 6 mm Hg for patients with mitral stenosis), but normal values for right ventricular end-diastolic volume index (normal 95 +/- 11, patients 81 +/- 9 ml/m2) and ejection fraction (normal 0.49 +/- 0.02, patients 0.58 +/- 0.04). Comparison of right ventricular function using group performance curves of stroke work versus end-diastolic volume revealed the slope of the mitral stenosis line to be significantly greater than the normal line. A plot of right ventricular stroke volume versus end-diastolic volume, which removes pressure from the performance index, revealed that the two groups have similar performance. Left ventricular function measured by ejection fraction was reduced in mitral stenosis. These data suggest that the right ventricle performs normally in patients with mitral stenosis with moderate pulmonary hypertension and maintains normal size and ejection fraction.