Left ventricular performance in mitral regurgitation assessed with systolic time intervals and echocardiography

Among 22 patients with isolated mitral regurgitation of various origins, systolic time intervals (preejection period [PEP] index, left ventricular ejection time [LVET] index and PEP/LVET) and echocardiographic measures of left ventricular performance (end-diastolic diameter [Dd], end-systolic diameter [Ds], and the percent change in minor axis diameter [%ΔD]) were calculated. The patients were classified into two groups, those with a normal or supernormal %ΔD (group I, 15 patients) and those with a decreased %ΔD (group II, 7 patients).

On group analysis, prolongation of the preejection period, shortening of the left ventricular ejection time and an increase in PEP/LVET was generally characteristic of patients with mitral regurgitation. These changes were accentuated when mitral regurgitation was complicated by echocardiographic evidence of diminished left ventricular contractile performance (%ΔD less than 30 percent). An increase in PEP/LVET to greater than 0.50 was consistently associated with abnormal left ventricular performance, whereas a normal PEP/LVET ratio reflected normal or supernormal left ventricular performance.

An inverse linear relation was found between PEP/LVET and %ΔD. When compared with previous data on the relation of these variables among patients without valve insufficiency, PEP/LVET proved to be increased for any level of %ΔD in mitral regurgitation. The state of digitalization did not appear to influence the relation between PEP/LVET and %ΔD. The use of echocardiographic measurements augments the determination of systolic time intervals in the analysis of left ventricular performance in patients with mitral regurgitation.     

Accuracy of systolic time intervals in detecting abnormal left ventricular performance in coronary artery disease

Sixty-six consecutive patients with a history of previous myocardial infarction and 48 patients with angina pectoris without evidence of previous myocardial infarction, all of whom had diagnostic coronary arteriography and left ventriculography, were studied in a prospective analysis of the accuracy of noninvasively determined systolic time intervals as a measure of global left ventricular performance. Forty-one patients who were evaluated for atypical chest pain and found to have normal coronary arteries and left ventricular performance served as control subjects. Six methods of statistical analysis were employed in assessing the accuracy of systolic time intervals in relation to the left ventricular ejection fraction: (1) analysis of variance, (2) cumulative distribution analysis, (3) correlation, (4) sensitivity and specificity, (5) percent agreement, and (6) logistic regression analysis. These tests permitted comparison between the systolic time intervals and the angiographic left ventricular ejection fraction. Analysis of variance revealed identical discriminating power for the ratio of the preejection period to left ventricular ejection time (PEP/ LVET) and left ventricular ejection fraction in separating the normal group and patients without previous myocardial infarction from the patients with previous myocardial infarction. The preejection period and left ventricular ejection time corrected for heart rate were less discriminating than left ventricular ejection fraction or PEP/LVET. The cumulative distribution plots for the left ventricular ejection fraction and PEP/LVET in the three groups of patients were remarkably similar. The correlation of PEP/LVET and left ventricular ejection fraction for all three groups of patients was 0.84. The sensitivity and specificity of the PEP/LVET in relation to the left ventricular ejection fraction were 88 and 96 percent, respectively. The overall agreement between the two measures in detecting the prevalence of abnormality in global left ventricular performance in subgroups of patients was 92 percent. By logistic regression analysis the two measures had equal capacity in discriminating the patients with previous myocardial infarction from the control group.The multiple strategies of comparison employed in this study document the close relation of measures of the timing of the left ventricular contraction cycle by systolic time intervals and estimates of the extent of left ventricular contraction by ejection fraction in patients with coronary artery disease. It is concluded that these measures afford independent and complementary methods of defining the presence of abnormal left ventricular performance in the resting supine patient with coronary artery disease.     

Contractile and biochemical effects of coronary reperfusion after extended periods of coronary occlusion.

The effects of coronary reperfusion on recovery of regional myocardial contractility and high energy pegmental changes in myocardial contractility were measured by means of a strain gauge-tipped, two-pronged catheter probe that measures myocardial fiber shortening. The curves of contraction are sensitive to the effects of ischemia. Coronary occlusion resulted in a rapid replacement of fiber shortening by passive fiber lengthening. If coronary occlusion was released and blood flow restored within 45 minutes, myocardial contractility returned promptly; adenosine triphosphate and creatine phosphate values were restored to normal. With coronary occlusion of 1 hour or longer, contractility failed to return in the immediate postperfusion period, but delayed return was recorded after 2 weeks of reperfusion. The extent of such recovery varied with the duration of preceding occlusion. Thus, reperfusion after 1 hour of occlusion was followed by return of fiber shortening over the entire reperfused region. With 2 hours of occlusion, recovery occurred over 75 percent of the reperfused myocardium. With 3 hours of occlusion followed by reperfusion, recovery of contractility was only partial, comprising approximately 60 percent of the reperfused region. High energy phosphate content of the reperfused myocardium showed a similar pattern of recovery. With occlusion of longer duration, reperfusion failed to restore contractility to any significant extent. These findings indicate that reperfusion after coronary occlusion of 1 to 3 hours may restore contractility over a period of 2 weeks, but the extent of such recovery diminishes with the increase in the duration of occlusion.     

Prognostic significance of systolic time intervals after recovery from myocardial infarction

This study tested the hypothesis that left ventricular global performance as assessed from systolic time intervals provides a prognostic indicator in patients with coronary artery disease. The ratio of preejection period to left ventricular ejection time ($\text{PEP}\text{LVET}$) was determined in 136 patients an average of 14.3 months (standard deviation 2 months) after a clinically documented acute myocardial infarction. The patients were followed up a minimum of 24 and an average of 43 ± 15 months. Coronary arteriography was performed within 48 hours of determination of the $\text{sol}\text{PEP}\text{LVET}$ ratio. The cumulative 5 year survival rate was 70 percent for the entire series; it was 93 percent for patients with a normal $\text{PEP}\text{LVET}$ ratio (0.42 or less) and 57 percent for patients with an abnormal ratio (greater than 0.42) (p < 0.001).There was diminishing cumulative survival with increasing extent of coronary arterial obstruction (p < 0.01). Among patients with a normal $\text{PEP}\text{LVET}$ ratio and one, two or three vessel disease, the 5 year survival rate was 97, 92 and 87 percent, respectively. Among patients with an abnormal $\text{PEP}\text{LVET}$ ratio, the respective rates were 82, 51 and 41 percent. Multivariate analysis of factors shown to vary significantly between groups with a normal or abnormal $\text{PEP}\text{LVET}$ ratio or to have independent prognostic value (age greater than 60 years, angina pectoris, dyspnea, multiple sites of myocardial infarction on electrocardiography, third sound gallop, and cardiothoracic ratio greater than 0.5 on chest roentgenography) revealed that only a cardiothoracic ratio greater than 0.5 added significant predictive information to that of the $\text{PEP}\text{LVET}$ ratio. The presence of dyspnea, a third or fourth sound gallop and a cardiothoracic ratio greater than 0.5, alone or in combination, did not permit accurate segregation of the patients with a normal or abnormal $\text{PEP}\text{LVET}$ ratio.Determination of the $\text{PEP}\text{LVET}$ ratio permits stratification of patients with a previous myocardial infarction into groups with markedly divergent survival patterns. The level of resting left ventricular performance in such patients constitutes a more potent prognostic indicator than does the extent of coronary arterial occlusive disease.     

Usefulness of systolic time intervals in coronary artery disease

This review summarizes current knowledge concerning the value of systolic time intervals in coronary artery disease. Although the usual pattern of prolongation of the preejection period (PEP) and shortening of the left ventricular ejection time (LVET) characteristic of left ventricular failure is seen in acute myocardial infarction, the systolic time intervals (as well as all other measures) are profoundly influenced by adrenergic hyperactivity characteristics of this disorder. Adrenergic stimulation normally shortens both the PEP and LVET indexes and decreases the PEP/LVET ratio. The degree of shortening of electromechanical systole (QS₂) is directly related to the excessive adrenergic tone. Patients with the greatest systolic time interval abnormalities have a poorer prognosis, a greater incidence of congestive heart failure and more abnormalities of directly measured indexes of left ventricular performance.The systolic time intervals are useful for assessing left ventricular performance in chronic coronary artery disease as well. In chronic coronary artery disease the PEP/LVET ratio and angiographically determined left ventricular ejection fraction are closely correlated (r = ? 0.76), but the level of this correlation is less than that in other forms of left ventricular disease.The left ventricular ejection time index is prolonged after exercise in patients with angina pectoris when compared with findings in normal subjects. Failure of the ischemic ventricle to respond to adrenergic stimulation is the most likely mechanism. Addition of the postexercise left ventricular ejection time to standard treadmill stress testing identifies a significant number of patients (23 percent) who would have had false negative results by electrocardiographic criteria alone. In addition, this index provides confirmatory evidence in those with apparently positive electrocardiographic test data. p]The systolic time intervals have been useful in assessing both medical and surgical therapy in coronary artery disease. The test can be performed repeatedly and provides a measure of both left ventricular performance and extent of adrenergic hyperactivity. Thus, evaluation of therapy represents the most useful future application of systolic time intervals.     

Antinuclear antibodies (ANA): Immunologic and clinical significance

The methods currently used for the detection of ANA have been analyzed, with emphasis on their practical application to the diagnosis of the CTD. The use of the indirect IF-ANA test was recommended as a screening procedure to detect ANA. The need to standardize the technique using a single substrate and fluorescent conjugates with uniform $\text{F}\text{P}$ ratios was stressed. Most importantly, the value of titrating ANA for the diagnosis of the CTD was discussed. ANA titers higher than 1/500 are usually very significant clinically, often found in spontaneous or drug-induced SLE and few other CTD. The immunologic aspects of ANA and their potential value as aids in the diagnosis and management of the CTD were discussed. Anti-nDNA antibodies have been found to have a high degree of specificity for SLE and high titers of these antibodies correlate well with low levels of serum complement and severity of kidney involvement. The spectrum of ANA in the sera from patients with SLE has been expanded with the finding of anti-Sm antibodies which, when detected by gel precipitation with prototype serum, have been found so far only in SLE. Some of these antibodies have been found to have prognostic significance. Patients with MCTD and a group of patients with SLE have high titers of serum ANA with specificity for an RNase-sensitive component of ENA. The group of SLE patients defined by the presence of these antibodies (anti-Mo) have a better prognosis and in general develop only mild nephritis or have no kidney involvement at all. High titers of pure antinucleolar antibodies probably are found almost exclusively in the sera of patients with scleroderma. Some ANA have organ specificity, and GS-ANA have been found in all patients with Felty's syndrome and in a large proportion of patients with RA.One of the great advances in the field has been the recognition that ANA can be induced in the human and in experimental animals by the use of a number of therapeutic agents. Some of these agents can also induce a clinical picture resembling spontaneous SLE, though kidney involvement does not occur or is extremely mild. It is interesting that the whole spectrum of ANA can be found in drug-induced LE except anti-nDNA antibodies which have been associated to the pathogenesis of immune complex nephritis in spontaneous SLE.There is no doubt that research on ANA has contributed a great deal to the understanding of the CTD and will continue to be a valuable tool for the clinician and the investigator.     

Morphometry of cardiac hypertrophy induced by experimental renal hypertension.

A method for determining the mean volume of cells within a tissue has been applied to the measurement of endocardial and epicardial myocytes in the left ventricle of normal and hypertensive rats. The technique is based on nuclear counts per unit area in tissue slices of different known thicknesses. It measures the mean cell volume per nucleus and has been combined with electron microscopic morphometry. Compared with the epicardial regions, the normal endocardial regions contained 30 percent more myocytes, 27 percent less interstitial space, 48 percent less capillary volume, 17 percent less capillary surface and the same capillary length per unit of tissue volume. In terms of both the relative and absolute volumes and surface areas of their organelles, the cytoplasmic composition of normal endocardial and epicardial myocytes was nearly identical.After 1 to 4 weeks of hypertension induced by renal arterial constriction, endocardial myocytes enlarged from 10,370 ± 410 to 12,520 ± 490 μ m³ whereas epicardial myocytes enlarged from 12,600 ± 1,600 to 17,300 ± 1, 100 μm³. The number of myocytes and the total length of capillaries remained constant. The epicardial region enlarged 37 percent with proportional increases of myocyte and interstitial volumes. In contrast, the endocardial enlargement was only 26 percent, consisting of 21 percent hypertrophy of myocytes and a 55 percent increase in interstitial components. Expansion of capillary lumens accounted for much of the interstitial enlargement throughout the myocardium. Hypertrophy of myocytes in the epicardial region was accompanied by a reduced mitochondria to myofibril ratio and disproportionately large increases (two- to three-fold) in both smooth endoplasmic reticulum and T system volume and surface area. On a cell basis the morphometric characteristics of myocytes from hypertensive rats are significantly different from normal, and significant differences occur between the inner and outer layers of the myocardium for practically every cytoplasmic component.     

Plasma norepinephrine in congestive heart failure.

Resting plasma concentrations of norepinephrine, dopamine-beta-hydroxylase enzyme activity and peripheral blood lymphocyte beta adrenergic receptor sensitivity to isoproterenol as reflected in cyclic 3′,5′-adenosine monophosphate (cAMP) generation were studied in patients with congestive heart failure due to atherosclerotic heart disease or to congestive cardiomyopathy or hypertensive cardiovascular disease. Systolic time Intervals were also measured in nonhypertensive patients and correlated with the plasma norepinephrine concentration. Control patients were hospital employees without a previous history of heart disease or hypertension, and were matched for age to eliminate the effect of increasing age on the plasma norepinephrine concentration.The results of this study clearly demonstrate that the plasma norepinephrine concentration is directly related to the degree of left ventricular dysfunction in patients with congestive heart failure. When the systolic time intervals were correlated with the plasma norepinephrine levels, a significant prolongation of the preejection period was observed with progressively increasing plasma concentrations of norepinephrine. The reverse was true for the left ventricular ejection time, which demonstrated a significant Inverse relation with the plasma norepinephrine concentration. The ratio of the preejection period to the left ventricular ejection time, which is a reflection of left ventricular function, significantly increased with increasing levels of plasma norepinephrine. In addition, plasma lymphocytes from patients with the greatest degree of left ventricular dysfunction failed to generate normal amounts of cAMP after beta adrenergic receptor stimulation with isoproterenol. It Is suggested that beta adrenergic receptors are desensitized in these patients and that this desensitization contributes to the observed alterations in myocardial contractility.     

Effect of prolonged intense endurance training on systolic time intervals in patients with coronary artery disease

We studied the effect of exercise training (ET) on systolic time intervals (STI) in 13 patients with coronary artery disease (CAD). All patients trained for at least 10 months. They exercised three times/week at 50% to 70% of maximal oxygen uptake (VO2max) for the initial 3 months and at least four times/week for approximately 50 minutes at 70% to 90% of VO2max thereafter. A significant training effect was documented by an increase in VO2max from 26.0 +/- 4.3 to 37.2 +/- 5.8 ml/kg/min (p less than 0.01), a lower heart rate (HR) at rest, and a lower blood pressure and HR during submaximal work. The indices of total electromechanical systole (QS2I) and left ventricular ejection time (LVETI) did not change. However, pre-ejection period index (PEPI) decreased from 137 +/- 9 msec to 129 +/- 9 msec (p less than 0.01). PEP/LVET decreased from 0.373 +/- 0.028 to 0.342 +/- 0.032 (p less than 0.01). Left ventricular end-diastolic dimension and posterior wall thickness, measured echocardiographically, were increased after training. We conclude that exercise training may improve myocardial performance in some patients with CAD.     

Left ventricular function at high altitude examined by systolic time intervals and M-mode echocardiography

To better understand the effects of high-altitude hypoxia on cardiac performance, healthy lowlandresiding volunteers were studied in 2 groups: 10 subjects after acute ascent to 12,500 ft (3,810 m) (acute group) and 9 subjects after chronic exposure for 6 weeks to 17,600 ft (5,365 m) and 11,000 ft (3,353 m) (chronic group). Systolic time intervals and M-mode echocardiograms were recorded at low and high altitudes. Heart rate was 21% greater at high altitude for all subjects. Preejection period/left ventricular ejection time (PEP/LVET) increased by 16% in the acute group and by 22% in the chronic group. Heart size was smaller at high altitude in both groups, with left atrial and left ventricular (LV) diameters decreasing by 10 to 12%. These changes were statistically significant (p ≤ 0.01). Despite the increase in PEP/LVET, echocardiographic measurements of LV function (percent fractional shortening and mean normalized velocity of circumferential fiber shortening) remained normal. LV isovolumic contraction time was shorter at high altitude, suggesting heightened, rather than depressed, contractility. LV function does not appear to deteriorate at high altitude. Alterations in systolic time intervals probably result from decreased preload, as reflected by smaller heart size, rather than from heart failure or depressed LV contractility.     

Left ventricular function in patients with and without myocardial infarction and one,two or three vessel coronary artery disease

Ninety-six patients with chest pain were studied to determine the relation between left ventricular function and severity of coronary artery disease in patients with and without a history of myocardial infarction. Coronary arteriography was performed obtaining cineangiograms (60 frames/sec) and large roll film angiograms (2 to 6 frames/sec) for precise definition of the coronary anatomy. The criteria for diagnosis of myocardial infarction were a typical history, a rise and fall in serum glutamic oxaloacetic transaminase levels and evolutionary S-T segment changes associated with Q waves of at least 0.03 second. Left ventricular function was assessed by measurement of left ventricular end-diastolic pressure and volume, and left ventricular ejection fraction, mass and compliance. Fifteen patients had normal findings; 81 were classified according to number of diseased vessels and presence or absence of myocardial infarction. There were no group differences in age or heart rate. Left ventricular end-diastolic pressure was abnormally increased in patients with three vessel disease and myocardial infarction. Left ventricular end-diastolic volume was increased and the ejection fraction was reduced in patients in each vessel disease group with myocardial infarction. Although ejection fraction was reduced in patients with three vessel disease without myocardial infarction, it was further reduced when infarction occurred. Left ventricular mass increased in patients with three vessel disease with or without myocardial infarction. Values for ventricular compliance were reduced in all patients with myocardial infarction and were lower in those with two and three vessel disease and infarction than in those with two and three vessel disease without infarction. These findings suggest that a previous history of myocardial infarction needs to be considered together with anatomic abnormalities of the coronary arteries in assessing cardiac performance in patients with ischemic heart disease. In patients with one, two or three vessel coronary artery disease, a previous myocardial infarction significantly alters left ventricular performance; the ejection fraction is a more sensitive measurement of left ventricular function than left ventricular end-diastolic pressure or volume.     

Significant coronary artery disease detected by amyl nitrite and systolic time intervals

The relation between changes in left ventricular systolic time intervals with amyl nitrite (AN) inhalation and the severity of coronary artery disease (CAD) was evaluated in 77 patients who underwent catheterization because of chest pain. In 25 subjects with normal coronary angiograms (control group), AN inhalation increased the ejection time (ET), shortened the prejection period (PEP) and increased the ET/PEP markedly. In the 52 patients with CAD (CAD group), the ET/PEP changed insignificantly after AN. The difference between the 2 groups was significant (p < 0.001). At cardiac catherization, the increase of left ventricular dP/dt after AN in the control group was significantly larger than that in the CAD group. Although a positive correlation between changes in ET/PEP with AN and ejection fraction at rest was noted in patients with 1-vessel CAD, no such correlation was noted in those with multivessel CAD. This suggests that factors in addition to pump function, such as the degree of CAD, influence the effect of AN inhalation on systolic time intervals. When an increase of less than 30% in ET/PEP occurs with AN Inhalation, the presence of significant CAD can be detected with a sensitivity of 92%, a specificity of 84% and the predictive value of 92%. The AN inhalation test is safe and simple, and thus could serve as a stress test for evaluating the presence and severity of significant CAD.     

Primary acquired sideroblastic anemia preceding monoclonal gammopathy and malignant lymphoma

An elderly white man presented as a typical example of primary acquired Sideroblastic anemia in 1965. Three years later, the peripheral blood smear revealed the presence of atypical and immature lymphocytes. Two small palpable lymph nodes were noted in the right axilla and a possibly enlarged spleen on intravenous pyelogram in 1969; however, a biopsy specimen of the lymph node failed to show any evidence for malignant lymphoma. In 1970, a monoclonal gammopathy, immunoglobulin G (IgG), subclass G₁, kappa, Gm (afb) and InV (1-) was documented. At that time, the presence of kappa light chain in urine was also noted. The patient died of bronchopneumonia in February 1971. Autopsy revealed malignant lymphoma, poorly differentiated type, involving the abdominal lymph nodes and spleen. This unusual development of malignant lymphoma in a patient with primary acquired sideroblastic anemia has not, to the best of our knowledge, been recorded previously. Whether or not primary acquired sideroblastic anemia represents a prelymphoplasmaproliferative or other premalignant blood disorder can be settled only by longitudinal studies in a large number of such patients.     

Left ventricular dynamics during long-term digoxin treatment in patients with stable coronary artery disease

Ten patients with stable coronary artery disease who did not have clinical congestive heart failure and had recovered (3 or more months) from coronary bypass graft surgery were given both intravenous and oral digoxin. Left ventricular performance was assessed weekly for 3 control weeks, during 4 weeks of long-term oral digoxin treatment and during 2 to 3 weeks of recovery. Serial noninvasive measurements of velocity of circumferential fiber shortening, ejection fraction, end-diastolic volume and cardiac output were obtained with computer-assisted fluoroscopic analysis of the motion of surgically implanted mid wall myocardial markers that outline the left ventricular cavity. During 4 weeks of oral digoxin therapy, mean serum digoxin levels were maintained between 1.2 ± 0.1 and 1.4 ± 0.1 ng/ml (mean ± standard error of the mean). Mean velocity of circumferential fiber shortening increased 15.6 percent from 0.65 ± 0.05 to 0.75 ± 0.05 circumferences/sec (P < 0.001) and ejection fraction increased 8.5 percent from 0.51 ± 0.03 to 0.55 ± 0.03 (P < 0.001). End-diastolic volume and cardiac output were not changed significantly. The inotropic response to oral digoxin was similar during the 4th week of treatment to that seen during the first week and the mean inotropic effect of chronic oral digoxin was not significantly less than that achieved by administration of 1 mg intravenously over 15 minutes. These data suggest that chronic oral digoxin treatment exerts a sustained inotropic effect on the nonfailing heart that persists for at least 4 weeks and is equivalent to that achieved with rapid intravenous digitalization.     

Prevalence of clinically occult cardiomyopathy in chronic alcoholism

The mean absolute heart weight and mean heart weight to body weight ratio of a group of 43 alcoholics, screened from 1,970 consectuive autopsy reports at the Detroit General Hospital by selecting alcoholics with only ethyl alcohol abuse as an etiology of heart disease, are compared to those of a group of similarly selected age-matched nonalcoholic controls. None of the alcoholics was clinically suspected of having had cardiomyopathy. The statistically significant increased mean absolute heart weight and heart weight to body weight ratio of the alcoholic group reflected the presence of subclinical alcoholic cardiomyopathy. In addition, several of the patients in the alcoholic group displayed gross and microscopic cardiac pathologic changes consistent with alcoholic cardiomyopathy occurring in the absence of cardiomegaly.