James K. Alexander

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.

The cardiac pathology of chronic exogenous obesity.

Appraisal of the gross and microscopic anatomy of the heart was carried out at necropsy in 12 subjects (six men, six women) with marked chronic obesity. In each case the observed heart weight was considerably greater than that predicted at ideal body weight. Nine of the 12 subjects were found to have increase in left ventricular wall thickness, and two increase in right. The increases in heart weight and ventricular wall thickness were due to muscle hypertrophy involving the left ventricle or both left and right ventricles. Neither isolated nor predominant right ventricular hypertrophy was observed.It has been concluded that myocardial hypertrophy is a more specific and significant anatomic alteration in the hearts of very obese subjects than are the previously reported findings of excess epicardial fat and fatty infiltration of the myocardium. The relationship between chronic augmentation of the work of the heart in these subjects and the development of cardiac hypertrophy has been discussed. The findings in this study have been interpreted as providing further support for the propositions that manifestations of myocardial insufficiency do occur in very obese subjects without evidences of other heart disease, that these manifestations are those of predominant left ventricular or biventricular failure, and that isolated cor pulmonale does not develop in the absence of pulmonary embolization.

Echocardiographic assessment of left ventricular function with special reference to normalized velocities.

The concept of “normalized velocity’ has been applied in this study to the echocardiographic (echo) assessment of left ventricular (LV) function in 87 patients. The following normalized velocities were calculated from the ultrasound recording of LV wall motion: 1) the mean circumferential fiber shortening rate (mean VCF), 2) the mean normalized posterior wall velocity (VPW), and 3) the mean normalized interventricular septal velocity (VIVS). Systolic ejection fraction (SEF), and mean (non-normalized) posterior wall velocity (PWV) were also determined. There were 19 patients with normal LV function, 5 with atrial septal defect (mean VCF, VIVS and SEF were not calculated in these patients), 16 with LV volume overload, 29 with myocardial disease, 6 with hypertrophic cardiomyopathy and 12 with coronary artery disease (CAD). Single plane cineangiographic (angio) determinations of mean VCF and SEF were obtained in 50 of the 87 patients (including all 12 patients with CAD).Mean VCF and SEF done by echo correlated very well with mean VCF and SEF done by angio in the patients without CAD (r = 0.94 and 0.91, respectively). Mean VCF (by echo or by angio) adequately separated normal from abnormal LV function. Although correlation between mean VCF and SEF was good, mean VCF was reduced while SEF was well preserved in several patients. In spite of LV asynergy, most of the patients with CAD had good correlation between echo and angio measurements of mean VCF and SEF. Although PWV correlated with echo and angio mean VCF in the patients without CAD, the overlap of normal and abnormal values made PWV an unreliable index of LV function. In contrast, VPW proved to be a reliable indicator of LV performance in patients without LV asynergy. Agreement between VPW and mean VCF (by echo or angio) was seen in 94% of the patients; in the presence of CAD, however, greater discrepancy was seen between these two measurements. Agreement between VIVS and VPW was present in 90% of the patients without CAD, but in only 58% of the patients with CAD.The analysis of LV wall motion by echocardiography utilizing the “normalized velocity’ concept appears to be a rational and practical method for evaluation of LV performance. In the absence of asynergy, VPW provides a reliable index of LV performance which may be of particular value when abnormal septal motion precludes the determination of SEF and mean VCF. In the presence of asynergy, however, mean VCF, VPW and VIVS may reflect only the performance of the visualized segment of myocardium.

Cardiovascular Effects of Weight Reduction

Weight reduction programs usually improve the exercise capacity of patients with chronic exogenous obesity. However, the reversibility of left ventricular hypertrophy and dysfunction associated with obesity is unknown. Accordingly, an analysis was made of hemodynamic data obtained by cardiac catheterization and standard chest roentgenograms in nine markedly obese patients before and after weight loss of 39 to 84 kg (24 to 55% of control weight) over periods of 4 to 34 months. In each case body oxygen uptake (360 to 297 ml/min), blood volume (7.8 to 6.1 liters), cardiac output (7.9 to 6.2 liters/min), and arteriovenous oxygen difference (4.6 to 4.0 vol. %) were significantly reduced after weight loss. Systemic arterial pressure declined (102 to 87 mm Hg) while systemic vascular resistance changed insignificantly (1,067 to 1,141 dynes-sec-cm-5). In seven subjects comparable chest roentgenograms before and after weight reduction revealed decrease in the cardiothoracic ratio, suggesting a reduction in left ventricular dimensions. These results have been interpreted as indicating that the circulatory effects of gross obesity are largely reversible with weight loss. Despite reductions in left ventricular stroke work, stroke volume, and cavity size at rest, the average left ventricular filling pressure rose with exercise to a comparable and abnormal level (20 mm Hg) both before and after weight loss. Thus, evidence of left ventricular dysfunction persisted, suggesting that myocardial hypertrophy and reduced ventricular compliance did not regress significantly with weight loss over periods as long as 3 years.

ANALYSIS OF THE RESPIRATORY RESPONSE TO CARBON DIOXIDE INHALATION IN VARYING CLINICAL STATES OF HYPERCAPNIA, ANOXIA, AND ACID-BASE DERANGEMENT

Individuals with cor pulmonale secondary to chronic pulmonary emphysema tend to have pulmonary ventilation which is less than normal both at rest and during exercise, despite the presence of factors ordinarily making for increased ventilation such as anoxemia and acidosis (1), and despite the fact that these ventilatory levels may be appreciably less than the observed maximum breathing capacity. Moreover, the ventilatory response to increased CO2 in the inspired air may be less than normal in certain patients with pulmonary emphysema (2-5). These observations

Observations on some clinical features of extreme obesity, with particular reference to cardiorespiratory effects☆

Abstract The nature, incidence and pathogenesis of some clinical features in fifty patients with extreme obesity have been analyzed, utilizing several kinds of relevant information. Exertional dyspnea (84 per cent), joint pains (72 per cent) and somnolence (52 per cent) were common symptoms. The incidence of blood pressure elevation (58 per cent) and peripheral edema (64 per cent) was relatively high, and roentgenographic evidence of cardiomegaly was quite regularly present, as indicated by comparison of the observed transverse cardiac diameter with that predicted for the ideal body weight by the Ungerleider-Clark table. Since one-third of the patients were normotensive, it was concluded that blood pressure elevation is by no means an invariable accompaniment of obesity, even when extreme. No correlation was found between the level of systemic blood pressure and the amount of excess weight. Comparison of blood pressure measurements by direct intra-arterial recording and the standard cuff method yielded falsely elevated values using the cuff 25 per cent of the time, but in only 8 per cent of the cases was this discrepancy large. Actually, the cuff method gave a falsely low estimate as frequently as it did a high one, so that a high reading obtained with the cuff was usually a valid indication of systemic arterial hypertension. The frequency and severity of peripheral edema could not be correlated with the amount of excess weight or with the level of the central venous pressure. Although elevated intra-abdominal pressure and varicose veins may play a role, mechanisms of edema formation in obesity seem poorly defined at present. Incidence and degree of somnolence were not correlated with amount of excess weight, arterial oxygen saturation, central venous pressure, or level of cerebral blood flow and oxygen consumption. Analysis of the relation between arterial carbon dioxide tension and degree of somnolence showed that all six patients with carbon dioxide retention had a tendency to somnolence. However, neither the presence of somnolence nor its severity could be related to the level of arterial carbon dioxide tension. The occurrence of pronounced somnolence without carbon dioxide retention has been taken as evidence denying a causal relationship involving carbon dioxide retention alone. It has been concluded that while carbon dioxide retention may aggravate a tendency to somnolence, the chief mechanisms responsible for development of somnolence in the obese state are not well defined at this time. Polycythemia was not observed in this series, although its occurrence in obese patients is well recognized. On the basis of our experience and published reports of larger series it has been concluded that the incidence of polycythemia is 5 per cent or less in patients with uncomplicated obesity. Mechanisms of dyspnea in the obese state have been reviewed in the light of demands upon the respiratory apparatus and its response. There was poor correlation between the severity of the dyspnea and the observed body weight or the amount of excess weight. A concept of the sequence of events leading to cardiomegaly and congestive heart failure in patients with extreme obesity has been advanced, and the so-called Pickwickian syndrome of obesity has been discussed with particular reference to the development of hypoventilation and cor pulmonale. Presently available data suggest that the incidence of hypoventilation is of the order of 10 per cent in patients with uncomplicated extreme obesity, as found in this study, and therefore this feature is representative at best of only a small segment of this obese population. Congestive heart failure, although uncommon, may occur in extremely obese patients with or without elevation of systemic arterial pressure. It is usually characterized by high cardiac output and insufficiency of both ventricles, predominantly the left. It has been concluded further that there is as yet no convincing evidence to indicate that uncomplicated obesity of extreme degree gives rise to the development of isolated cor pulmonale.

Obesity and cardiac performance

Abstract In association with consistent increases in stroke volume and a high incidence of systemic and/or pulmonary arterial hypertension, the cardiac work of very obese patients at rest was considerably greater than that predicted for normotensive subjects at ideal body weight. Although this change was effected chiefly by increased left ventricular work, and the latter was roughly correlated with the amount of excess body weight, variable increases in right ventricular work resulted in a lack of correlation between total cardiac work and the amount of excess weight. Though pulmonary hypertension secondary to an increase in left ventricular filling pressure usually occurred in the very obese patients of this series under conditions of moderate exercise, the increment in cardiac output per unit increment in oxygen consumption with exercise was within normal limits. Because of the need to move excess body weight, at any given level of activity the cardiac workload was considerably greater for the obese subjects than for individuals at ideal body weight. Cardiac enlargement and increased heart weight were found quite regularly in very obese subjects, increasing in rough proportion to the amount of excess body weight. The increased heart weight was due to muscular hypertrophy involving the left ventricle or both the left and right ventricles. Neither fatty infiltration of the myocardium nor isolated right ventricular hypertrophy was observed. Cardiac failure occurred in 8 per cent of the extremely obese patients in this series, involving a high cardiac output and left ventricular or biventricular insufficiency. It has been proposed that myocardial hypertrophy and failure derive from the increased cardiac workload present at rest and during exercise. Heart failure due to obesity generally responded well to bed rest, digitalis, diuretics, dietary sodium restriction and measures usually effective in managing heart failure due to other causes. Effective long term therapy necessarily involved weight reduction.

Obesity and Coronary Heart Disease

Obesity is commonly cited as a risk factor for the development of coronary heart disease (CHD). Epidemiologic studies tend to support this contention, particularly those focusing on patients with central obesity. Such studies however, are imprecise and prone to misclassification bias. Angiographic and post mortem studies have demonstrated little or no correlation of total fat mass and coronary atherosclerosis except in those with abdominal obesity. There is a strong association of obesity, particularly central obesity, and traditional risk factors for CHD such as hypertension, type II diabetes mellitus, and dyslipidemia. There may also be an association between obesity and several nontraditional risk factors such as hyperhomocystinemia, elevated Lp(a) levels and factors that increase thrombogenesis. Obesity may also alter endothelial function. Weight loss, although associated with favorable modification of multiple risk factors for CHD, has not been shown to independently and definitively reduce CHD risk.

Echocardiographic determination of left ventricular stress-velocity relations.

The time course of left ventricular (LV) circumferential stress and fiber shortening velocity (Vcf) were determined at 20 msec intervals in 30 patients from simultaneous recordings of LV pressure (micromanometer) and LV dimensions (echography). In 12 patients with normal LV function, endocardial and midwall maximal (max) Vcf, Vcf at peak stress, and endocardial mean Vcf were significantly greater than in eight patients with myocardial disease. Peak stress was less in the normal subjects (mean equal 241 gl/cm2, range 180 to 310 g/cm2) than in those with myocardial diseases (mean equals 371 g/cm2, range 280 to 513 g/cm2). Vcf was reduced in five out of seven patients with chronic LV volume overload, while peak stress ranged from normal in three to increased in four. Max Vcf, mean Vcf, and peak stress were normal in three patients with chronic LV pressure overload; Vcf at peak stress was normal in two. Good correlation was observed between angiographic determinations of mean Vcf and endocardial max Vcf, Vcf at peak stress and mean Vcf. Induced changes in preload in five patients (dextran infusion at constant heart rate) produced a 12.2 per cent increase in peak stress (P small than 0.05), and insignificant changes in max Vcf (3.7 per cent increase, P = NS), in Vcf at peak stress (5 per cent decrease, P smaller than 0.05), in mean Vcf (0.7 per cent increase, P = NS). Increasing afterload with angiotensin in seven patients (peak stress increased by 45 per cent, P smaller than 0.01) reduced max Vcf, Vcf at peak stress and mean Vcf by 33 per cent, 39 per cent respectively. Lowering afterload in one patient (amyl nitrite) produced an increase in Vcf. Improvement in Vcf was observed in all instances during positive inotropic stimulation (isoproterenol in three normals, digoxin in four with myocardial disease). Thre response of endocardial and midwall Vcf to loading and contractility were similar. In man Vcf is an index of myocardial contractility which is affected minimally by changes in preload but responds inversely to changes in afterload. Its sensitivity to acute afterload changes may, at times, limit its clinical applicability.

Left atrial enlargement. Echocardiographic assessment of electrocardiographic criteria.

SUMMARY 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 V, 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.