Biomedical subjects
J K Alexander
Publications and source records attributed to J K Alexander.
Suppression of defects in cyclic adenosine 3',5'-monophosphate metabolism in Escherichia coli.
Strain MM6-13 (ptsI suc lacI sup) of Escherichia coli contains a suppressor of the succinate-negative phenotype. In MM6-13, sup caused enhanced growth in glycerol, maltose, melibiose, and succinate media and increased activity of beta-galactosidase and tryptophanase relative to an isogenic strain without sup. In strain A61 (cya sup), sup partially suppressed cya. Cyclic guanosine monophosphate increased beta-galactosidase activity sevenfold in A61 and enabled this strain to grow on maltose, galactose, succinate, and arabinose. Strain A61 responded to much lower concentrations of cyclic adenosine monophosphate than cyclic guanosine monophosphate. It appears that sup is located in the crp locus. These results suggest that sup mutants have an altered cyclic adenosine monophosphate receptor protein which is activated by cyclic guanosine monophosphate and has an increased affinity for cyclic adenosine monophosphate.
Recurrent infective endocarditis: analysis of predisposing factors and clinical features.
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Lysis of Escherichia coli mutants by lactose.
Growth of Escherichia coli strain MM6-13 (ptsI suc lacI sup), which as a suppressor of the succinate-negative phenotype, was inhibited by lactose. Cells growing in yeast extract-tryptone-sodium chloride medium (LB broth) were lysed upon the addition of lactose. In Casamino Acids-salts medium, lactose inhibited growth, but due to the high K+ content no lysis occurred. Lysis required high levels of beta-galctosidase and lactose transport activity. MM6, the parental strain of MM6-13, has lower levels of both of these activities and was resistant to lysis under these conditions. When MM6 was grown in LB broth with exogenous cyclic adenosine monophosphate, however, beta-galactosidase and lactose transport activities were greatly increased, and lysis occurred upon the addition of lactose. Resting cells of both MM6 and MM6-13 were lysed by lactose in buffers containing suitable ions. In the presence of MG2+, lysis was enhanced by 5 mM KCl and 100 mM NaCl. Higher slat concentrations (50 mM KCl or 200 mM NaCl) provided partial protection from lysis. In the absence of Mg2+, lysis occurred without KCl. Lactose-dependent lysis occurred in buffers containing anions such as sulafte, chloride, phosphate, or citrate; however, thiocyanate or acetate protected the cells from lysis. These data indicate that both cations and anions, as well as the levels of lactose transport and beta-galactosidase activity, are important in lysis.
Surgery in active infective endocarditis.
Controversy persists concerning the role of early surgical intervention in severe infective endocarditis (IE). We therefore reviewed 163 episodes of well-documented IE in which 32 cardiac operations were performed during the active phase of IE. Congestive heart failure (CHF) was the principal indication for surgery in 88% (28/32); systemic emboli, 1/32; and persisting sepsis, 3/32. Staphylococcus and enterococcus were the most common infecting organisms in the operative group (44% and 16% respectively). Surgical mortality (11/32,37%) did not differ (p greater than 0.05) from medical mortality (26/131,20%). All 11 operative deaths occurred in patients moribund prior to surgery, including three with preoperative cardiac arrest. Surgical patients undergoing preoperative cardiac catheterization demonstrated marked CHF: a mean left ventricular end-diastolic pressure of 25.3 mm Hg. The mean cardiac index in 8/11 surgical deaths was lower (p less than 0.05) vs surgical survivors: 2.21/min/m2 vs. 3.21/min/m2. Postoperative complications were rare in the 21 surgical survivors. There were no episodes of continued infection, prosthetic dehiscence, or advanced heart block; only one paravalvular leak; and one systemic embolus. These findings emphasize the high medical and surgical mortality in patients with IE, suggest that delayed operative intervention may be a major causative factor resulting in a high surgical mortality, and justify an aggressive surgical approach in patients with valve dysfunction and heart failure. These data indicate that survivors of surgical intervention during active IE have eradication of infection and few postoperative complications.
Recurrent infective endocarditis in a drug addict. Multiple separate episodes in nine years.
Multiple episodes of documented recurrent infective endocarditis occurred in an habitual drug abuser. The six recurrences represent the largest known number reported in a single patient. The case illustrates many characteristics of infective endocarditis and serves to emphasize that recurrent infections are likely if endocarditis risk factors are not eliminated.
Percentage of shortening of the echocardiographic left ventricular dimension. Its use in determining ejection fraction and stroke volume.
The percentage of shortening of the echocardiographic left ventricular dimension (% delta D) was prospectively evaluated in 42 patients without detectable asynergy during diagnostic cardiac catheterization and was found to correlate well with angiographic ejection fraction (r = 0.90). Ejection fraction was calculated as the product of % delta D X 1.7 or as % delta (D2), both formulae having similar degrees of accuracy and a better correlation with the angiographic determination than conventional formulae. Ejection fractions (angiographic and echocardiographic) of 51 percent or greater were always associated with a % delta D of 30 percent or more. In five patients the echocardiographically derived ejection fractions were normal (greater than or equal to 51 percent), while the angiographic ejection fractions were reduced; four of these patients had valvular regurgitation. End-diastolic volumes were calculated from end-diastolic echocardiographic dimensions utilizing a linear regression equation derived from correlating the end-diastolic echocardiographic dimension with the end-diastolic volume in 27 patients without valvular regurgitation (end-diastolic echocardiographic dimension ranged from 3.7 to 8.2 cm). The value for stroke volume determined as the product of calculated end-diastolic volume times ejection fraction correlated with the angiographically determined stroke volume (r = 0.88; standard error of estimate, +/- 11 ml) better than the value for stroke volume derived from conventional echocardiographic formulae.
Community education for cardiovascular health.
To determine whether community health education can reduce the risk of cardiovascular disease, a field experiment was conducted in three northern California towns. In two of these communities there were extensive mass-media campaigns over a 2-year period, and in one of these, face-to-face counselling was also provided for a small subset of high-risk people. The third community served as a control. People from each community were interviewed and examined before the campaigns began and one and two years afterwards to assess knowledge and behaviour related to cardiovascular disease (e.g., diet and smoking) and also to measure physiological indicators of risk (e.g., blood-pressure, relative weight, and plasma-cholesterol). In the control community the risk of cardiovascular disease increased over the two years but in the treatment communities there was a substantial and sustained decrease in risk. In the community in which there was some face-to-face counselling the initial improvement was greater and health education was more successful in reducing cigarette smoking, but at the end of the second year the decrease in risk was similar in both treatment communities. These results strongly suggest that mass-media education campaigns directed at entire communities may be very effective in reducing the risk of cardiovascular disease.
Left ventricular compliance: mechanisms and clinical implications.
Left ventricular diastolic compliance is determined by the level of operating pressure and the diastolic pressure-volume relation. This relation is curvillinear and the slope of a tangent (operative chamber stiffness) to the pressure-volume curve increases as the chamber progressively fills. Such preload-dependent changes in compliance occur during any acute alteration in ventricular volume. At a given diastolic pressure, operative chamber stiffness (or its reciprocal, operative chamber compliance) is determined by the relative values for ventricular volume and muscle mass and by the stiffness of a unit of myocardium. Thus, there may be a leftward shift of the diastolic pressure-volume curve (increase in the modulus of chamber stiffness) as a consequence of ventricular hypertrophy or an increase in the stiffness of heart muscle itself (increase in modulus of muscle stiffness). To distinguish between hypertrophy and stiff muscle, it is useful to examine the modulus of chamber stiffness, derived from pressure-volume data, together with the volume/mass ratio of the ventricle. In this fashion, changes in the modulus of chamber stiffness that are inappropriate for a given volume/mass ratio may be attributed to changes in the material properties of the heart muscle. Examples of clinical and experimental pressure-volume studies are presented to illustrate the variety of mechanisms by which acute and chronic changes in ventricular chamber compliance evolve during the course of clinical heart disease. The pathophysiology of pulmonary congestion is best understood by considering the factors responsible for producing changes in chamber stiffness of the ventricle, whereas an examination of muscle stiffness is likely to provide more insight into the extent of irreversible functional and structural defects of the myocardium.
Aortic valve closure: echocardiographic, phonocardiographic, and hemodynamic assessment.
The temporal relationship between the closure of the aortic valve (AoV) and the onset of the aortic component of the second heart sound (A2) was defined by simultaneous recording of AoV echogram, phonocardiogram (PCG), and electrocardiogram in 25 subjects. Ten subjects had no heart disease (normal); 15 suffered from various cardiac conditions other than AoV disease (patients). The point of coaptation (C) of the AoV cusps to the onset of A2, the C-A2 interval, was measured to the nearest 5 msec. in 125 cycles. Fifty-eight cycles had a C-A2 of 10 msec., and 47 cycles had a C-A2 of 15 msec. The remainder were distributed at intervals below 10 or above 15 msec. The average C-A2 interval was 11.48 +/- 0.38 msec. (mean +/- 1 S.D.). A similar distribution pattern was observed when the total number of cycles was divided into "normal" and "patient" groups. In 3 subjects, simultaneous equisensitive (catheter-tip micromanometer) left ventricular and central aortic pressures, PCG, and AoV echograms were recorded. C-A2 ranged from 0 to 10 msec.; the interval between left ventricular and aortic pressure at the level of the incisura-hangout interval-ranged from 8 to 20 msec. Inhalation of amyl nitrite in one subject produced a significant fall in arterial pressure, accompanied by prolongation of the hangout interval from 10 to 20 msec. and of the C-A2 interval from 0 to 8 msec. Thus, the C-A2 interval is an integral part of the hangout time. Data suggest that A2 does not originate from the coaptation of the aortic valve cusps per se, but is related to events that occur at the time of or slightly after coaptation.
Alterations in the coronary circulation of man following ascent to 3,100 m altitude.
Alterations in coronary blood flow associated with adaptation to high altitude were examined. Three normal men native to low altitude were studied, first at sea level, and again after 10 days' sojourn at 3,100 m altitude. During rest at high altitude, a 32% decrease in coronary blood flow was largely offset by a 28% increase in coronary arterial O2 extraction to maintain myocardial O2 delivery. The increase in O2 extraction resulted mainly from a decrease in coronary sinus blood O2 content and saturation. However, coronary sinus O2 tension remained constant, implying a decrease in the affinity of hemoglobin for O2. These observations are consistent with the hypothesis that coronary blood flow is regulated to maintain constant myocardial tissue O2 tension (as reflected here by coronary sinus blood O2 tension). The absence of a decrease in coronary sinus O2 tension or a decrease in myocardial lactate extraction imply that myocardial hypoxia did not develop. Therefore, myocardial hypoxia is not the basis for the decrease in cardiac stroke volume at high altitude reported previously and also observed in the present study.
Influence of acute changes in preload, afterload, contractile state and heart rate on ejection and isovolumic indices of myocardial contractility in man.
To determine the sensitivity of several isovolumic and ejection phase indices of myocardial contractility to loading, inotropic stimulation and heart rate in man, 14 patients (pts) were studied during cardiac catheterization with simultaneous recordings of left ventricular (LV) pressures and ultrasound dimensions. Measurements were made of instantaneous and mean circumferential fiber shortening velocity (VCF), maximal (max) rate of LV pressure rise (dP/dt), dPHdt divided by end-diastolic circumference [(dP/dt)/C], (DP/dt)/C divided by aortic valve opening pressure [(dP/dt/CP], PEAK CONTRACTILe element velocity (VCE) using total LV pressure, VCE extrapolated to zero total pressure (Vmax), VCE at a developed pressure of 10 mm Hg (VCEDP10) and dP/dt at a common isovolumic developed pressure of 40 mm Hg [(dP/dt)/DP40]. Resulta are expressed in per cent change of the mean for the group. Acute preload increase (8.6% increase in end-diastolic circumference) with volume expansion at constant heart rate in 7 pts produced insignificant changes in VSF, an 8.3% increase in max dP/dt, no change in (dP/dt)/C, a variable response in (dP/dt)/CP, 18% reduction in peak VCE, 16% reduction in Vmax, 14% increase in VCEDP10, and a 10% increase in (dP/dt)/DP40. An acute increase in afterload produced by angiotensin in 8 pts (44% increase in peak stress) led to a 38% decrease in VCF, a 2.5% increase in max dP/dt, no significant change in (dP/dt)/C, a 26% reduction in (dP/dt)/CP, variable responses in peak VCE and Vmax, an 11% increase in VCEDP10 and minor changes in (dP/dt)/DP40. All of the contractility indices were augmented significantly by isoproterenol and atrial pacing. In a given patient, max, dP/dt appears to be useful in the assessment of acute changes in inotropic state since the magnitude of its response to abrupt changes in preload is small and to afterload insignificant. Normalizing max dP/dt for end-diastolic circumference assures better stability during loading with good sensitivity to inotropic stimulation. VCF may be used whenever changes in afterload are minimal. The isovolumic measurements of VCE (regardless of whether total or developed pressure is used) lack sufficient stability during acute changes in loading conditions to warrant their use in the quantitative assessment of acute changes in inotropic state.
Left atrial enlargement. Echocardiographic assessment of electrocardiographic criteria.
A comparison of electrocardiographic manifestations of left atrial enlargement (LAE) and left atrial size by echocardiography was made in 307 patients in sinus rhythm. Electrocardiographic criteria used were L:P wave duration in lead II equal to or greater than 0.12 sec; Va: the ratio of the duration of negative terminal P in V1 to the P-R segment equal to or greater than 1.0; Vb: a negative P terminal force in V1 less than -0.03 mm sec. The echocardiographic diagnosis of left atrial enlargement was based on 1) transverse dimension greater than 4.0 cm; or 2) a ratio of transverse atrial to transverse aortic root dimension greater than 1.17. In the presence of left atrial enlargement, a combination of criteria occurred more often than a single criterion. The overall predictive index of the electrocardiogram for left atrial enlargement was 63% (excluding criterion Vb raised probability to 80%); and that for absence of left atrial enlargement was 78%. The index of coarse versus fine fibrillary waves was unreliable in predicting left atrial enlargement. Changes in P wave morphology may be used as a reasonably specific but less sensitive indicator of left atrial enlargement.
Postventriculotomy aneurysm and left ventricular dysfunction following closed mitral commissurotomy.
A ventricular aneurysm at the site of a previous transventricular commissurotomy for mitral stenosis was diagnosed in a 39 year old female. Catheterization data showed abnormal left ventricular response to exercise and to increased afterload. Death occurred following mitral valve replacement. At autopsy no cause other than left ventricular aneurysm could be established to explain left ventricular dysfunction.
Prinzmetal's variant angina: hemodynamic and angiographic observations during pain.
Hemodynamic and angiographic data obtained during pain from four patients with Prinzmetal's variant angina are reported. The left ventricular pressure-time index did not increase before or during attacks of angina in three of the four patients; left ventricular systolic performance was impaired during pain in all three. In one of these three patients left ventricular pressure-volume data obtained during angina suggested a reduction in diastolic compliance; in another, pain and S-T segment elevation were present during coronary arterial spasm. The fourth patient had an increase in both arterial blood pressure and heart rate before an attack; in this patient coronary arterial spasm could not be demonstrated during the period of pain and S-T elevation. The data presented suggest that hemodynamic factors that increase the myocardial oxygen requirements are absent and that coronary arterial spasm is present in some, but not all, patients with variant angina.
Diastolic compliance of the left ventricle in man.
Two coordinates of left ventricular end-diastolic pressure (P) and volume (V) were provided by the infusion of angiotensin in 22 patients. The slope (k) of the ln P-V relation, coupled with knowledge of the operating (end-diastolic) pressure allows determination of end-diastolic volume compliance (dV/VdP). Estimates of end-diastolic compliance from a single coordinate of pressure and volume compared well (r equals 0.90) with the two coordinate method, whereas for specific compliance (deltaV/V1 deltaP) appeared to be misleading in cases of idiopathic hypertrophic subaortic stenosis and congestive cardiomyopathy. Since volume compliance is determined in part by the operating pressure, compliance may be reduced in small, normal or enlarged ventricles. Left ventricular linear compliance was derived from volume compliance and was normalized for left ventricular wall thickness. The product of linear compliance and end-diastolic stress provides an index of myocardial strain, termed "muscle fiber stretch," which may be related to systolic performance and thus allow comparison of length-performance relations in ventricles with normal and abnormal compliance.
Genetic analysis of succinate utilization in enzyme I mutants of the phosphoenolpyruvate: sugar phosphotransferase system in Escherichia coli.
Studies on the reversion characteristics of Escherichia coli strains carrying various mutations in the pts region have led to the recognition of a mutation, suc-1, with a previously undescribed phenotype. Strains carrying the suc-1 mutation grow normally on most sources of carbon but are unable to utilize succinate effectively. The suc-1 mutation can be separated genetically from the tightly linked ptsI6 mutation. Reversion of suc-1 mutants for growth on succinate yields interesting classes of suppressor mutations.
Dynamic determinants of letf ventricular diastolic pressure-volume relations in man.
Left ventricular (LV) diastolic pressure (P), volume (V), and rate of change of volume (dV/dt) were determined at 16.7 msec intervals in 17 patients (simultaneous micromanometer and single plane volume angiography). Four patients had mitral stenosis with atrial fibrillation and 13 patients (three normal, two congestive cardiomyophathy, three LV hypertrophy, and five coronary artery disease) were in normal sinus rhythm. Maximum early diastolic filling rates (max dV/dt) in the normal and cardiomyopathy patients were similar and ranged from 269 to 370 cc/m-2/sec; in coronary artery disease and LV hypertrophy, max dV/dt ranged from 197 to 290 cc/m-2/sec and 213 to 255 cc/m-2/sec respectively; in mitral stenosis, max dV/dt ranged from 215 to 270 cc/m-2 sec. The peak filling rate during atrial systole ranged form 60 to 240 cc/m-2/sec in the 13 patients with sinus rhythm. The instantaneous diastolic P-V data were fit by an exponential equation (P = be-kV) and the P-V relation throughout diastole was represented by the best fit line. The rate constant (k) in the equation was highest in the patient with IHSS and lowest in those with large dilated hearts. In mitral stenosis with atrial fibrillation the fit of the equation to the P-V data appeared better than in the patients with normal sinus rhythm. Peak ventricular filling rate during atrial systole varied directly with LV volume distensibility at the onset of atrial systole (r = 0.64). Data suggest that dynamic mechanical properties of the LV influence the diastolic P-V relations and that pressure "deviations" (deltaP) from the best fit line during atrial systole may be related to viscous drag. In a given ventricle the velocity dependence of deltaP appears to be modified by the volume distensibility of the ventricle. Variable rates of filling may preclude the assumption of an exponential relation between P and V throughout diastole and therefore may limit estimates of diastolic distensibility or compliance which rely on such an assumption.