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.     

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.     

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.     

Left ventricular performance in coronary artery disease evaluated with systolic time intervals and echocardiography

Simultaneous determinations of systolic time intervals (preejection period index [PEPI], left ventricular ejection time index [LVETI] and ratio of preejection period to left ventricular ejection time [PEP/LVET]) and echographic measures of left ventricular performance (percent change in minor axis diameter [%ΔD], circumferential shortening rate [Vcf] and end-diastolic diameter [Dd]) were obtained in 25 normal subjects and 37 patients with previously documented transmural myocardial infarction. The group with previous infarction demonstrated significant (P < 0.001) differences from the normal group in each of the noninvasive measures. PEP/LVET and %ΔD were the most sensitive measures of left ventricular dysfunction. Deviation from the normal range in these measures occurred, respectively, in 70 and 65 percent of patients without dyspnea or fatigability (20 patients) and in 85 percent of those without angina pectoris (13 patients). Abnormalities in systolic time interval and echocardiographic measures were related to the severity of dyspnea and fatigability but not to that of angina. Neither the presence of phonocardiographically documented third or fourth sound gallops nor an abnormal cardiothoracic ratio by chest roentgenogram reliably detected patients with abnormal left ventricular performance. The range of abnormality in left ventricular performance did not differ between patients with prior anterior or diaphragmatic myocardial infarction. The frequency of abnormal performance was greatest among patients with combined sites of prior infarction. Among 26 patients studied by coronary arteriography, abnormal left ventricular performance as determined by values for PEP/LVET and %ΔD occurred in fewer than 30 percent of those with 70 percent or greater obstruction of one coronary artery and in more than 80 percent of those with two or three vessel involvement. There was a high correlation between systolic time intervals, %ΔD and Vcf, the closest correlation occurring between PEP/LVET and %ΔD (r = ?0.93). These data document the sensitivity of the noninvasive systolic time intervals and echographic measures and their superiority over current clinical bedside methods in evaluating left ventricular performance in patients with prior myocardial infarction.     

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.     

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.     

Platelet alpha 2 adrenoreceptors in chronic congestive heart failure

Patients with chronic congestive heart failure (CHF) are known to have elevated plasma concentrations of norepinephrine. Although this elevation of catecholamines in plasma may facilitate myocardial contractility, it may also be toxic to the myocardium in the long term. The alpha 2 adrenoreceptor located on noradrenergic nerve terminals regulates neuronal norepinephrine release by feedback inhibition. This receptor is also located on human blood platelets. This study determines the status of platelet alpha 2 adrenoreceptors in 16 patients with CHF (class I and II in 7 and class III and IV in 9) and in 26 normal volunteers. Specific high-affinity binding of the alpha 2 agonist 3H-clonidine and the alpha 2 antagonist 3H-yohimbine was used to determine the number (Bmax) of alpha 2 receptors and the dissociation constant (KD) for the 2 ligands. In the control population, the Bmax (in fmol/mg protein) for 3H-clonidine was 33 +/- 2 and for 3H-yohimbine was 165 +/- 12. There was a 25% difference in the maximum number of specific binding sites for 3H-clonidine in the class III/IV group (Bmax 24 +/- 2, p less than 0.05) and a 43% difference in the maximum number of specific binding sites for 3H-yohimbine (Bmax 94 +/- 9; p less than 0.005). There was a smaller but nonsignificant difference in the number of receptors on platelets from patients in the class I and II group. The KD's were similar in all 3 groups. These differences correlated well with the increases in plasma norepinephrine levels between the normal group (273.8 +/- 44.1 pg/ml) and the class III/IV group (1333.5 +/- 244.9, p less than 0.0005). This study supports the hypothesis that increased levels of circulating norepinephrine in CHF lead to a decrease in platelet alpha 2 adrenoreceptors. Further studies should be performed to determine whether pharmacologic stimulation of these receptors might lead to a decrease in the neuronal release of that norepinephrine which might be toxic to the myocardium. Monitoring of platelet alpha 2 adrenoreceptor number may provide a guide to therapy of CHF.     

Cardiocirculatory effects of afterload reduction with oral trimazosin in severe chronic congestive heart failure.

Because improved long-term oral vasodilator therapy for chronic congestive heart failure is needed, the cardiocirculatory effects of the new antihypertensive quinazoline derivative, trimazosin, were evaluated with use of concomitant cardiac catheterization and forearm plethysmography in nine patients with severe chronic congestive heart failure due to coronary disease. After ingestion of 100 to 300 mg (average 172 mg) of trimazosin, the greatly elevated left ventricular filling pressure decreased from 30 to 23 mm Hg and the lowered cardiac index rose from 2.02 to 2.59 liters/min per m2. Considerable improvement in cardiac function occurred within 1 hour after ingestion of trimazosin; peak efficacy was achieved after 2 hours and persisted in the 3rd hour. Heart rate was unchanged and systemic blood pressure was mildly reduced. Because pump performance was enhanced while indexes of myocardial oxygen consumption declined, ventricular efficiency increased. Vascular relaxation was produced in both the systemic resistance and capacitance beds, with venodilation slightly more prominent. This clinical investigation of the acute hemodynamic effects of trimazosin objectively demonstrates that the drug provides considerable hemodynamic benefit in cardiac dysfunction and is therefore a potentially salutary agent for treatment of patients with chronic severe congestive heart failure.     

Effect of cyclic nucleotides on mitogen. Responsiveness of lymphocytes from patients undergoing dialysis.

Lymphocytes from 10 asymptomatic patients undergoing hemodialysis and from eight control subjects were repeatedly cultured with exposure to various concentrations of cyclic nucleotides and theophylline in addition to mitogen. The blastogenic response of the patients' lymphocytes was inhibited by molar concentrations of dibutyryl cyclic AMP which had much less or no inhibitory effected on the response of the control subjects' lymphocytes. This suppressive effect was not potentiated by theophylline. Cyclic GMP enhanced the proliferative response of the patients' lymphocytes as well as that of the controls. In contrast to absolute counts per minute per culture, the suppression by dibutyryl cyclic AMP of mitogen-induced blastogenesis noted in this study clearly separated the in vitro behavior of the patients' lymphocytes from that of the controls' lymphocytes and may serve as a useful marker of cellular dysfunction in such patients.     

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.     

Hemodynamic effects of nitroglycerin ointment in congestive heart failure

The hemodynamic effects of nitroglycerin absorbed transcutaneously from an ointment base were determined in 10 patients with chronic congestive heart failure (9 with ischemic heart disease and 1 with cardiomyopathy). The response was characterized by a decrease in pulmonary capillary wedge pressure from an average of 30 to 19 mm Hg, and an increase in cardiac index from 1.7 to 2.2 liters/min per m², with concomitant decreases in systemic and pulmonary vascular resistance and an increase in venous capacitance. Mean arterial pressure decreased from 85 to 80 mm Hg, and heart rate remained unchanged. The hemodynamic effects persisted for 3 to 6 hours. These results indicate that nitroglycerin ointment is a hemodynamically potent vasodilating agent with potential value in the therapy of congestive heart failure.     

Comparison of hemodynamic actions of pirbuterol and dobutamine on cardiac function in severe congestive heart failure

There is considerable interest in the development of beneficial oral inotropic agents for sustained ambulatory management of patients with severe chronic congestive heart failure. Therefore, the hemodynamic actions of the oral beta adrenergic receptor agonist pirbuterol and of intravenous dobutamine were compared in nine patients with severe heart failure. Both agents produced similar effects on ventricular pump function: The cardiac index was markedly increased from 1.8 to 2.6 liters/min per m² (p < 0.005) by dobutamine and from 1.8 to 2.9 liters/min per m² (p < 0.001) by pirbuterol; stroke index was increased from 24 to 32 ml/beat per m² (p < 0.02) by dobutamine and from 23 to 35 ml/beat per m² (p < 0.001) by pirbuterol; the stroke work index was increased from 19 to 27 g-m/m² (p < 0.005) by dobutamine and from 20 to 28 g-m/m² (p < 0.005) by pirbuterol. However, although dobutamine did not change mean blood pressure or left ventricular filling pressure (p < 0.05), pirbuterol modestly decreased mean blood pressure from 83 to 75 mm Hg (p < 0.02) and moderately decreased left ventricular filling pressure from 23 to 18 mm Hg (p < 0.005). Dobutamine reduced total systemic vascular resistance 22 percent from 2,049 to 1,582 dynes s cm^?5 (p < 0.001), whereas pirbuterol reduced this index 42 percent (p < 0.05 versus dobutamine) from 2,068 to 1,150 dynes s cm^?5. Neither agent altered heart rate or the heart rate-systolic blood pressure product (p < 0.05).Thus, oral pirbuterol has dobutamine-like beneficial hemodynamic effects on left ventricular pump function but causes a greater decrease in total systemic vascular resistance consistent with the combined inotropic and peripheral vasodilator actions of this oral beta adrenergic receptor agonist. These salutary hemodynamic responses suggest that oral pirbuterol may be useful for the prolonged treatment of severe chronic congestive heart failure.     

Prostacyclin therapy in patients with congestive heart failure

The acute hemodynamic effects of intravenous prostacyclin (PGI₂), in doses of 22 ± 11 ng/kg per min were studied in nine patients with severe congestive heart failure refractory to digitalis and diuretic drugs. After prostacyclin infusion, mean (±standard deviation) pulmonary capillary wedge pressure decreased from 21.0 ± 7.9 to 15.0 ± 6.6 mm Hg (p < 0.001), mean arterial pressure from 98.9 ± 12.8 to 76.2 ± 7.0 mm Hg (p < 0.001), systemic vascular resistance from 2,574 ± 384 to > 1,368 ± 283 dynes s cm^?5 (p < 0.001), pulmonary vascular resistance from 1,008 ± 451 to 443 ± 135 dynes s cm^?5 (p < 0.001) and pulmonary arteriolar resistance from 330 ± 111 to 189 ± 73 dynes s cm^?5 (p < 0.001). Heart rate increased from 78 ± 21 to 82 ± 24 beats/min (p = not significant [NS]), cardiac index from 2.0 ± 0.37 to 3.2 ± 0.59 liters/min per m² (p < 0.001) and stroke index from 27.6 ± 8.69 to 42.0 ± 0.62 cc/m² (p < 0.001). With prostacyclin, moreover, coldness of the limbs and face disappeared, and patients felt warmth and mild flushing of the face. After prostacyclin, plasma norepinephrine levels, renin activity and aldosterone concentrations rose from 824 ± 375 to 880 ± 468 pg/ml (NS), 0.68 ± 1.36 to 0.95 ± 1.21 ng/ml per h (NS), and 6.64 ± 2.50 to 6.38 ± 2.88 ng/dl (NS), respectively, while plasma epinephrine increased from 140 ± 80 to 250 ± 154 pg/ml (p < 0.025).