Contribution of External Forces to Left Ventricular Diastolic Pressure: Implications for the Clinical Use of the Starling Law

The Starling law of the heart states that the more the left ventricle fills with blood, the more volume it ejects. This dependence of cardiac output on filling volume was first recognized nearly a century ago [1] and remains at the core of the clinical evaluation and treatment of cardiac disorders. To apply this concept to the individual patient, the clinician must assess left ventricular filling, which is most often estimated using the pressure within the ventricle or the pulmonary capillary wedge pressure. However, these pressures do not solely reflect the blood volume within the left ventricle but are also influenced by extraventricular forces arising from the filling of the right heart and the constraining effects of the pericardium [2-8]. Altering these external forces can change left ventricular diastolic pressures, even when left-heart filling volume and, thus, cardiac output are unchanged [9-12]. Previous clinical and animal studies have established that altering extraventricular forces can change left ventricular diastolic pressures [9-12]. However, the quantitative importance of external contributions to the resting ventricular diastolic pressure remains controversial. In normal hearts, extraventricular forces are thought to have a small effect [13]; in chronically dilated hearts, the influence of these forces is thought to be reduced by simultaneous pericardial enlargement [14, 15]. Previous clinical studies probing external forces have been limited by the use of pharmacologic manipulations to alter these forces: These manipulations typically also lower left-heart volumes and arterial pressures, thereby complicating any interpretation of results [8-12, 16]. An alternative is to use mechanical interventions that suddenly lower external forces before they change left ventricular filling. For example, Slinker and colleagues [17] inhibited filling of the right heart within a single beat to evaluate ventricular interaction in normal animals. This is not feasible in humans, but an alternative method that can achieve similar effects is rapid obstruction of inferior vena caval inflow using a balloon catheter [18-20]. In the first few beats after balloon inflation, right atrial pressures often decrease almost to zero, although blood inflow to the left heart does not immediately diminish. This results in a sudden decrease in left ventricular diastolic pressures with minimal change in filling volumes [20]. As obstruction of venous inflow is sustained, filling of the left ventricle eventually decreases. The initial decrease in diastolic pressure, however, principally reflects the withdrawal of extraventricular forces. We used this maneuver to test the hypothesis that a considerable proportion of resting diastolic filling pressure stems from factors extrinsic to the left heart. We also tested whether this proportion would be diminished by chronic cardiac disease that would be expected to dilate the pericardium. Our results show that 30% to 40% of measured diastolic pressures result from forces external to the left ventricle and that this percentage is only slightly changed by cardiac disease. Methods Patients We studied 29 patients. Twelve had normal ventricular function confirmed by echocardiography, ventriculography, or both; an ejection fraction of at least 60%; and end-diastolic pressure of 20 mm Hg or less. All patients had been referred for diagnostic cardiac catheterization to evaluate atypical chest pain. Six patients had chronic idiopathic dilated cardiomyopathy with exertional dyspnea; ejection fraction of 40% or less; chamber dilation (short-axis diastolic dimension 6 cm); and a normal coronary angiogram. Five patients presented with dyspnea, pulmonary congestion, or both but had histories of hypertension and ventricular hypertrophy. Lastly, six patients had high-grade proximal coronary stenoses and recent histories of unstable or accelerated angina pectoris. No patients had had a myocardial infarction. The studies were done at the Johns Hopkins Medical Institutions, Baltimore, Maryland (n = 19); Veterans General Hospital, Taipei, Taiwan (n = 5); and the Instituto di Coracao, Sao Paolo, Brazil (n = 5). All patients provided informed consent, and the study protocol was approved by the human investigation committee of each institution. Procedure The method used to measure left ventricular pressure and volume with an intracardiac conductance catheter has been previously reported [18-20]. Each patient first had standard right- and left-heart catheterization. A multielectrode conductance (volume) catheter was then advanced to the left ventricular apex. A low-amplitude, high-frequency current was applied to electrodes located at the left ventricular base and apex, and resistances were measured at multiple intervening electrodes. This yielded a time-varying signal proportional to intracavitary chamber volume. A micromanometer (PC-330A, Millar, Inc., Houston, Texas) placed within the lumen of the catheter provided a simultaneous high-fidelity measurement of ventricular pressure. A custom-designed, large-balloon occlusion catheter (SP-09168, Cordis, Miami, Florida) was placed in the right atrium. Balloon inflation using 10 to 20 mL carbon dioxide and withdrawal of the catheter toward the proximal inferior vena cava produced rapid reversible decrease of cardiac filling. Pressure-volume data were measured continuously at steady state and immediately after the onset and continuation of inferior vena caval balloon occlusion. Occlusion was sustained for 10 to 15 seconds and then released. The conductance catheter volume signal was calibrated to the contrast left ventriculogram (single plane, right anterior oblique projection) by matching end-diastolic and end-systolic volumes. Ventriculogram volumes were estimated from the frames of maximal and minimal area, respectively. The corresponding catheter signal volumes were obtained as the averaged volumes during phases of isovolumetric contraction and relaxation. Data Analysis Left ventricular pressure-volume data from five consecutive end-expiratory cardiac cycles were averaged to yield a single pressure-volume loop (plot of instantaneous left ventricular volume on x-axis compared with simultaneous left ventricular pressure on y-axis). From these data, the stable resting diastolic pressure-volume curve [20], end-diastolic and end-systolic volumes, stroke volume and cardiac output, and ejection fraction were measured [19, 20]. The isovolumetric relaxation time constant, which indexes the rate of ventricular pressure decay, was also derived from these data [21]. Figure 1 shows an example of the left ventricular pressure-volume data used to assess the relative contributions of the intrinsic (due to properties of the left ventricle itself) and extrinsic components of resting left ventricular diastolic pressure. Figure 1A shows resting pressure-volume loops. During each cardiac cycle, data moved counterclockwise around the loop. Shortly after the obstruction of inferior vena caval inflow, left ventricular diastolic pressures decreased with little change in chamber volumes (Figure 1B). This downward shift of the diastolic pressure-volume relation primarily reflects the sudden decrease in external forces mediated by the extent of right ventricular filling. Continued obstruction of inferior vena caval inflow eventually decreased left ventricular volumes, shifting the pressure-volume loops leftward beat by beat (Figure 1C) and reducing systolic pressures and stroke volume (height and width of loops). This response is the manifestation of the Starling law. Note that after the initial near-parallel decrease of the left ventricular diastolic pressure-volume relation, the remaining diastolic data of subsequent beats occurred along a more or less single curve (Figure 1C). This relation was called the diastolic pressure-volume relation and reflects the intrinsic diastolic properties of the left ventricle. Figure 1. Measurement of the contribution of external forces to resting left ventricular diastolic pressures. The initial downward shift of diastolic pressure-volume data was taken as a measure of the contribution of external forces to resting diastolic pressure (Figure 1D). This downward shift was measured as the difference in pressure between initial resting beats and the diastolic pressure-volume relation at a common volume just before atrial contraction. At this point, relaxation of the left ventricle was more than 99% complete as judged by the isovolumetric relaxation time constant, and rapid filling and atrial contraction had minimal influence on diastolic pressures. Statistical Analysis Data are presented as means SD. Hemodynamic comparisons between patients with diseased and normal hearts were done using a multiple-comparisons analysis of variance. Data obtained before and after occlusion of the inferior vena cava were compared using a paired Student t-test. Results Clinical and Hemodynamic Characteristics of Patients Table 1 shows the clinical and major hemodynamic characteristics of the four groups of patients. Mean age was similar among all groups. Left ventricular end-diastolic pressure was significantly higher in each of the groups with disease than in the controls and averaged almost 20 mm Hg. Only patients with dilated cardiomyopathy had increased chamber volumes and decreased ejection fractions. Cardiac output and heart rate were reduced in the group with ischemia, probably because of concomitant -blocker therapy. Table 1. Clinical and Major Hemodynamic Characteristics of Study Patients* Contribution of External Forces to Resting Left Ventricular Diastolic Pressure Figure 2 shows the relation between left ventricular diastolic pressure obtained under resting conditions (LVPd) and the component of this pressure that is caused by forces external to the left ventricle (Delta Pd). Data from all groups of patients are combined into a single plot; each group is identified