Radionuclide Monitoring of Cardiac Adaptations to Volume Loading in Patients With Dilated Cardiomyopathy and Mild Heart Failure
Effects of Angiotensin-Converting Enzyme Inhibition
Background Cardiac adaptations to volume overload have been poorly investigated in heart failure. The aim of this study was to assess dynamic left ventricular responses to acute volume loading by continuous radionuclide monitoring in patients with asymptomatic to mildly symptomatic left ventricular dysfunction.
Methods and Results Left ventricular end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction (EF), and peak filling rate (PFR) were monitored by a radionuclide detector (Vest) before and during volume expansion (sodium chloride, 0.9%, 0.25 mL · kg−1 · min−1 for 2 hours) in 10 patients with idiopathic dilated cardiomyopathy (DCM) and mild heart failure (New York Heart Association class I or II, ejection fraction <50%). The patients were studied off treatment and after 6 to 8 weeks of oral treatment with enalapril (5 mg/d). A control group of 11 age- and sex-matched healthy volunteers (N group) was also studied. In the N group, volume loading caused prompt and sustained increases of EDV, EF, and PFR (all P<.001), whereas ESV was progressively reduced (P<.001), and heart rate and blood pressure did not change. In contrast, in DCM, EDV showed a smaller increase than in the N group (two-way ANOVA: F=5.98, P<.001), ESV increased (P<.001), and EF and PFR remained unchanged. After enalapril, the cardiac adaptations to volume loading were restored to normal. In particular, EDV, EF, and PFR increased (P<.001), and ESV was reduced (P<.001). In 6 additional DCM patients studied before and after 6 to 8 weeks of placebo treatment, left ventricular responses to volume loading remained unchanged.
Conclusions Left ventricular dynamic adaptations to acute volume loading are compromised in patients with idiopathic DCM and mild heart failure. These impaired responses are ameliorated by treatment with enalapril.
Symptoms and clinical signs of CHF depend largely on the inability to adequately increase cardiac output in response to augmented demand induced by exercise1 or volume overload.2 In the normal state, these adjustments of cardiac output are related primarily to increases in stroke volume resulting from recruitment of contractile or preload reserve.3 4 5 Therefore, the assessment of ventricular functional adaptations in response to increased preload may be particularly important in clinical conditions characterized by impaired contractile function, such as CHF secondary to cardiomyopathies.
Although several studies have addressed this issue with physical exercise,5 6 7 8 9 10 little is known about the hemodynamic adaptations to volume overload, which represents a hallmark of CHF. In this regard, we recently reported that remarkable abnormalities of cardiorenal responses are unmasked by acute isotonic volume expansion in patients with DCM of predominantly ischemic origin and asymptomatic to mildly symptomatic heart failure (NYHA class I or II).11 12 In particular, we showed an impaired cardiac endocrine response, as documented by the lack of atrial natriuretic factor secretion during volume loading. In addition, the enhancement of left ventricular systolic function induced by increased preload in healthy subjects was not observed in the cardiopathic patients.11 12
The recent development of ambulatory ventricular function radionuclide monitors, such as Vest,13 14 allows reliable, continuous, and noninvasive assessment of left ventricular function during different activities in healthy subjects15 16 as well as in patients with different types of heart disease.14 17 18 Such an approach may provide insights into ventricular performance on a sequential basis and hence noninvasive detection of transient adaptations of ventricular function as they may occur during volume overload.
The present study was designed to assess the dynamic left ventricular diastolic and systolic responses to a volume challenge in patients with asymptomatic to mildly symptomatic heart failure (NYHA class I or II). To avoid the potential interference of transient myocardial ischemia during acute cardiac loading, we studied only patients with idiopathic DCM. Left ventricular responses to acute volume overload were continuously monitored by Vest in these patients and in a control group of healthy subjects. In addition, the patients with DCM were studied again after long-term treatment with the ACE inhibitor enalapril or with placebo. Favorable effects of ACE inhibition on systemic hemodynamics,10 progression of ventricular dysfunction,19 and survival20 have been shown in patients with mild left ventricular dysfunction. Therefore, it is important to determine whether and how ACE inhibitors may influence the adaptations to increases of preload in this stage of the disease.
Study Subjects and Patients
The overall study population included 11 healthy volunteers and 17 patients with idiopathic DCM and chronic, stable, mild heart failure. The experimental protocol was approved by the ethical committee of our institution, and each subject gave written informed consent before entering the study.
The healthy group comprised 8 men and 3 women, ranging in age from 33 to 62 years (mean, 45.3±3.2 years). Normal status was established by history, physical examinations, and laboratory analyses, which included a blood count, serum glucose and cholesterol concentrations, indexes of renal and hepatic function, an ECG, and M- and B-mode echocardiograms. Ten patients with heart failure, 9 men and 1 woman 32 to 59 years old (mean, 46.2±2.6 years), who were recruited by selection of consecutive patients in the outpatient clinic for cardiovascular diseases of our institution, underwent the main study analysis of the responses in control conditions and after treatment with enalapril. The individual characteristics of these patients with DCM are reported in Table 1⇓. Exclusion criteria were any other major disease, ischemic heart disease, hypertension, atrial fibrillation or severe ventricular arrhythmia, renal failure, recent acute cardiac decompensation as defined by the sudden accumulation of pulmonary congestion or peripheral edema, valvular disease or significant mitral regurgitation, and cardiothoracic anatomy not allowing for satisfactory and reproducible echocardiographic recordings. The diagnosis of DCM was based on the exclusion of any obvious underlying cause of heart failure during routine evaluation. In particular, no patient had a history of angina or myocardial infarction, and all patients had undergone coronary angiography showing normal coronary arteries.
The definition of mild heart failure was based on the following criteria: (1) patients showed no reduction or mild reduction in their functional capacity according to the NYHA classification21 (class I or II); (2) there was mild to moderate limitation of exercise capacity as determined by cardiopulmonary exercise testing using a standard protocol (upright bicycling with a stepwise increase of 10 W/min) (mean exercise duration in our patients was 11.0±0.6 minutes; peak oxygen consumption averaged 19.0±2.2 mL · kg−1 · min−1); (3) echocardiographic end-diastolic left ventricular diameter was >56 mm (mean, 66.8±1.7 mm); and (4) left ventricular ejection fraction, as determined by equilibrium radionuclide angiography, was <50% (mean, 33.6±3.7%) on at least one measurement within 3 months before the study. At the time of their first visit to the outpatient clinic, 5 patients were under treatment with ACE inhibitors, while digitalis and diuretics were given to 4 and 3 patients, respectively.
An additional group of 6 patients with idiopathic DCM and mild heart failure was studied to investigate a potential influence of treatment with placebo on left ventricular adaptations to volume loading. These patients were recruited according to the same criteria, and their clinical characteristics are presented in Table 2⇓.
All drug therapy was discontinued at least 2 weeks before the patients entered the study, and ACE inhibitors were discontinued at least 6 weeks before the study. Alcohol, caffeine, smoking, and physical exercise were all prohibited within 24 hours of the study. All subjects were maintained on a daily diet containing 100 mEq sodium, 50 mEq potassium, and 1500 mL water. Daily 24-hour urine collections were analyzed for sodium, potassium, and creatinine excretion. When a satisfactory equilibrium between sodium and water excretion was achieved, the subject underwent the experimental session.
After the subject underwent an overnight fast, the study was begun at 8 am with the subject in a comfortable sitting position after voiding. The temperature (22°C) and the lights of the study room were maintained at constant levels.
The in vivo labeling of red blood cells was performed with 555 MBq (15 mCi) of 99mTc. In each subject, equilibrium radionuclide angiography was then obtained to determine basal peak filling rate and ejection fraction of the left ventricle. Immediately after radionuclide angiography, the Vest garment was placed over the subject’s chest and tightened to ensure stable contact. The Vest detector (Capintec, Inc) was positioned under gamma camera control as previously described in detail.22 A 2-minute static gamma camera image was obtained to confirm the adequacy of the Vest detector position. After 15 minutes of basal recordings, the isotonic volume expansion was started with an infusion of 0.9% NaCl solution at a flow rate of 0.25 mL · kg−1 · min−1 and maintained at a constant level for 120 minutes. This infusion rate of saline causes a safe and moderate increase of cardiac loading in patients with mild heart failure (20% to 40% increase of cardiac filling pressure) as observed in preliminary experiments performed in our laboratory. Arterial blood pressure was measured at 10-minute intervals throughout the study by a standard sphygmomanometric technique following the recommendations of the American Heart Association.23
To evaluate the effects of ACE inhibition on the responses to volume expansion, the patients were studied again after 6 to 8 weeks of treatment with enalapril (Merck & Co, Inc) (5 mg/24 h). This dosage of enalapril caused inhibition of ACE, as shown by significant increases of plasma renin activity (from 2.7±0.3 to 4.5±0.8 ng · mL−1 · h−1). The efficacy of this dosage of enalapril is also supported by previous data24 showing that 2.5 mg of the drug is sufficient to cause >80% inhibition of ACE activity in plasma and to effectively inhibit angiotensin I pressor response. The drug was administered every night at 8 pm.
In the additional group of 6 patients with idiopathic DCM and mild heart failure, radionuclide assessment of ventricular responses to volume loading was performed in control conditions and after 6 to 8 weeks of treatment with placebo (1 tablet every night at 8 pm).
Wide-angle, two-dimensional echoes were recorded with a phase-array sector scanner (77020 AC, Hewlett Packard Co). All studies were videotaped on 3/4-in. videocassette recorders equipped with a back-spacer search module, which allows frame-by-frame bidirectional playback. The video frame rate of the system is ≈60 frames per second. All patients were studied in the supine position with multiple views through the apical window. Two views, the apical four-chamber and apical two-chamber views, were selected for measurements. The left ventricular long axis (Lmax) was measured at end diastole as the longest major axis in either of the two apical views. The measurements of Lmax were rounded off to the closest whole number to ensure reproducibility. Left ventricular end-diastolic area (EDA) was measured by use of the largest of all the left ventricular minor axes measured. Left ventricular EDV, in milliliters, was calculated according to the single-plane ellipse method as EDV=8/3 (EDA)2/(π · Lmax).25 The same measurements were undertaken in end systole to calculate ESV. Ejection fraction was measured from the averages of EDV and ESV.25
Radionuclide angiography was analyzed with standard commercial software (General Electric).26 Left ventricular ejection fraction was computed on the raw time–activity curve, while peak filling rate was calculated after a Fourier expansion with four harmonics.26 Vest studies were analyzed as previously described.22 26 27 28 At the end of monitoring, data were reviewed for technical adequacy. Briefly, the average count rate (decay-corrected) of the entire study was displayed: if the curve had <10% deviation from a straight line, the Vest study was considered adequate. Radionuclide and ECG data were analyzed beat by beat and summed for 60-second intervals. Excellent agreement between Vest and radionuclide angiography in measuring ejection fraction and peak filling rate has been found for 60-second time averaging.22 Relative EDV was considered to be 100% at the beginning of the study and was subsequently expressed relative to this initial value. ESV was expressed relative to EDV. Ejection fraction was computed as the stroke counts divided by the background-corrected end-diastolic counts. Background was determined by matching the initial resting Vest ejection fraction value to that obtained by the gamma camera. This background value was then used throughout the remainder of each individual’s Vest data analysis. Peak filling rate was obtained from the Fourier curve and computed as the inflection point after end systole at which the second derivative shifts from positive to negative. The accuracy and reproducibility of this technique has been previously validated in our laboratory.22 26 In particular, the correlation coefficients between the measurements of the ejection fraction and the peak filling rate obtained with radionuclide angiography and with Vest were .99 and .88 (P<.01), respectively, and were maintained at the end of the monitoring period. Vest assessment of the ejection fraction and the peak filling rate within the same patients under steady-state conditions on different days of observation also showed significant correlations (r=.97 and r=.95, respectively, both P<.05). Finally, good reproducibility of left ventricular responses to different stimuli (nitroglycerin, tilt, handgrip, etc) studied by Vest has been reported by our laboratory.28
For analysis and graphical presentation of the data, values obtained at 5-minute intervals throughout the experiment were used.
Electrolyte levels in urine were measured by ion-selective electrodes (Beckmann E2A Na/K system). Plasma immunoreactive atrial natriuretic factor levels were measured in DCM patients by radioimmunoassay after extraction of plasma as previously described by our laboratory.29
Data are presented as mean±SEM. Analysis of data was performed with a commercial statistical package (SYSTAT, Inc).30 χ2 analysis was applied to compare the descriptive parameters of the study groups. Comparisons of the basal data of the groups was performed by unpaired t test or Wilcoxon rank test as appropriate. One-way ANOVA for repeated measures followed by post hoc analysis using linear contrasts was performed to detect changes over time within the same group.30 Between-group comparisons of the responses were tested by two-way ANOVA factoring by group and time.
Variability of Ejection Fraction at Rest
Variability in Vest determinations of left ventricular ejection fraction at rest without change in position, volume, or blood pressure status was determined by a weighted average of the changes in ejection fraction. In both experimental study groups, with the initial stable baseline ejection fraction used as the reference value, consecutive 1-minute collections of ejection fraction data during 15 minutes of resting were averaged for each subject. The mean changes in ejection fraction during this period of observation at rest were minimal in both groups: 1.5±0.4% in healthy subjects and 1.1±0.4% in DCM patients.
Characteristics of the Study Groups
The experimental study groups (patients with DCM and healthy subjects) were comparable with regard to demographic and clinical characteristics and renal function (Table 2⇑).
Effects of Volume Overload on Cardiac Dynamics in Healthy Subjects
As shown in Fig 1⇓, in healthy subjects, acute isotonic volume expansion induced a prompt increase of left ventricular EDV (P<.001) associated with a reduction of ESV (P<.001), which became significant after 30 minutes of volume load and lasted throughout the maneuver. In these subjects, left ventricular peak filling rate and ejection fraction showed a progressive and significant rise in response to volume expansion (both P<.001). A more detailed analysis of these responses showed that both parameters increased significantly after 30 minutes of saline load. Finally, heart rate (baseline, 70±3 beats per minute; 60 minutes, 67±2 beats per minute; and 120 minutes, 67±2 beats per minute) and systolic, diastolic, and mean blood pressures (baseline, 94±3; 60 minutes, 94±3; and 120 minutes, 96±2 mm Hg) did not change significantly throughout the study.
Effects of Volume Overload on Cardiac Dynamics in Patients With DCM: Influence of ACE Inhibition or Placebo Administration
In patients with DCM, acute volume overload produced an increase of left ventricular EDV that was significantly smaller than that observed in healthy subjects (two-way ANOVA: F=5.98, P<.001). Furthermore, in contrast to the pattern observed in healthy subjects, ESV showed a significant and sustained increase in response to saline load (two-way ANOVA: F=21.21, P<.001 versus healthy subjects) (Fig 2⇓, left). These responses were associated with unchanged peak filling rate and ejection fraction during volume overload. Both these parameters, which were lower than in healthy subjects at baseline (ejection fraction, 30.6±4% in DCM and 59.3±1% in healthy subjects, P<.001; peak filling rate, 1.15±0.1 EDV/s in DCM and 2.4±0.1 EDV/s in healthy subjects, P<.001), showed responses significantly different from those observed in healthy subjects during volume overload (two-way ANOVA: ejection fraction, F=8.43, P<.001; peak filling rate, F=6.93, P<.001) (Fig 2⇓, right).
A representative example showing the different trend plots of ventricular volumes, ejection fractions, and peak filling rates in a healthy subject and in a DCM patient during volume expansion is presented in Fig 3⇓.
Treatment with enalapril significantly increased left ventricular ejection fraction measured in DCM at the beginning of Vest monitoring, from 31.0±4% to 36.7±3%, while peak filling rate rose from 1.10±0.1 to 1.26±0.1 EDV/s.
Enalapril did not significantly modify basal heart rate (65±3 versus 71±5 beats per minute in the untreated patients) or systolic and diastolic blood pressures (121±2/79±3 versus 124±4/80±3 mm Hg). Pretreatment with enalapril, however, markedly modified the cardiac adaptations to volume overload in DCM. In fact, during the treatment with the ACE inhibitor, volume expansion was associated with a significant decrease of left ventricular ESV (P<.001), while EDV increased (P<.001) (Fig 4⇓, left). Enalapril pretreatment also restored significant increases in both peak filling rate and ejection fraction in DCM patients (both P<.001) (Fig 4⇓, right) during volume expansion. These responses were significantly different from those observed in the same patients before treatment with enalapril (two-way ANOVA: ejection fraction, F=2.62, P<.001; peak filling rate, F=2.91, P<.001). Heart rate (from 65±3 to 63±3 and to 64±3 beats per minute at 60 and 120 minutes, respectively) and systolic, diastolic, and mean blood pressures (from 93±2 to 91±2 and to 92±2 mm Hg at 60 and 120 minutes, respectively; P=NS) did not change significantly in response to volume expansion in DCM treated with enalapril.
Fig 5⇓ shows the left ventricular responses recorded by Vest in the additional group of 6 patients studied before and after treatment with placebo. Two-way ANOVA did not reveal significant differences between the responses of left ventricular volumes, ejection fractions, and peak filling rates observed before and after placebo.
The present studies demonstrate significant impairment of cardiac dynamics in response to acute blood volume expansion in patients with DCM and asymptomatic or mildly symptomatic left ventricular dysfunction. In fact, both diastolic and systolic left ventricular adaptations to volume overload were abnormal, as indicated by the impaired ability to augment left ventricular EDV and peak filling rate and to raise ejection fraction in response to volume loading, as observed in the healthy subjects. This inability to adequately adapt left ventricular filling and emptying to the increased load resulted in a progressive increase of ESV in DCM patients, in contrast to the reduction of this parameter observed in healthy subjects as a consequence of the enhanced ventricular performance. Finally, short-term chronic administration of the ACE inhibitor enalapril markedly improved both diastolic and systolic adaptations to volume overload.
These results substantially extend our previous observations obtained with the echocardiographic technique in patients with mild heart failure of different origin undergoing either acute or chronic volume overload.11 12 31 The present study is the first to provide detailed and dynamic analysis of the changes of ventricular function during a blood volume challenge in cardiopathic patients. In addition, the technical approach adopted, ie, an ambulatory radionuclide device (Vest),13 14 allowed us to obtain continuous, noninvasive monitoring of left ventricular diastolic function throughout the experimental period and to assess the sequence of cardiac adaptations in healthy subjects as well as their abnormalities in DCM patients.
In healthy subjects, volume loading produced prompt and sustained increases of left ventricular EDV and peak filling rate. These adjustments of diastolic function to increased preload most likely provided the basis for the enhancement of systolic performance, which is reflected by both the increase of the ejection fraction and the reduction of ESV. These changes of diastolic function observed in healthy human subjects confirm experimental observations obtained by Gaasch et al32 and Zile and Gaasch33 in the dog. These authors showed that abrupt increases of preload induced by rapid infusion of blood without prevention of the concurrent changes in afterload are associated with an increase of relaxation rate.
In contrast to the responses observed in healthy subjects, DCM patients were unable to adjust diastolic function in response to the increased preload, since left ventricular EDV showed only a modest and inconsistent increase, while peak filling rate failed to increase. Consequently, the systolic performance of the left ventricle was not adjusted to the modified loading conditions, as reflected by the lack of increase in ejection fraction, thus producing a paradoxical rise in ESV during volume loading.
Although our study did not include invasive measurement of intracardiac pressures, these data demonstrate that in patients with DCM and asymptomatic or mildly symptomatic heart failure, the ability to adjust left ventricular diastolic and systolic function is impaired, and they suggest an early exhaustion of the preload reserve mechanisms in heart failure, as previously described.10 11 12 Earlier studies by Konstam and coworkers10 reported that in patients with left ventricular systolic dysfunction and no signs or symptoms of congestive heart failure, left ventricular diastolic distension and stroke volume response to exercise are preserved despite loss of contractile function. In the same study, only patients with overt heart failure appeared to have exhausted preload reserve. The discrepancy with our findings may derive from the differences in the experimental approach (ie, exercise with consequent sympathetic activation versus volume loading) or technique of detection (equilibrium-gated radionuclide observations at specific times versus continuous radionuclide monitoring of ventricular function). In addition, in the study by Konstam et al,10 the patients were evaluated in the supine and not in the sitting position as in our study. Volume loading in the supine position may have facilitated venous return to the heart, thus producing greater diastolic filling with consequent increases in ventricular volumes and stroke volume,5 as observed in the patients with asymptomatic left ventricular dysfunction studied by Konstam et al.10
The reasons for impaired left ventricular diastolic dimensional and functional adaptations to increased volume load are not clarified by our study. Abnormal right ventricular dilation and ventricular interaction may explain the blunted increase of left ventricular filling during volume overload.34 35 36 An alternative explanation may be excessive chamber stiffness or exhausted/inadequate capacity for myocardial remodeling of the left ventricle in these patients.
Our findings provide evidence that the altered adaptations to acute blood volume expansion can be significantly improved by treatment with the ACE inhibitor enalapril. These results extend a previous report36 showing beneficial influence of acute ACE inhibition on resting left ventricular diastolic filling, especially in patients with enlarged right ventricles. In addition, our present data show that a short (6- to 8-week) treatment with enalapril may restore appropriate left ventricular diastolic filling and emptying during volume overload, while treatment with placebo does not significantly influence the ventricular responses to volume loading. The present studies, however, do not clarify whether this favorable effect on left ventricular function can be specifically attributed to ACE inhibition or whether it is common to other vasodilator compounds. Further studies are required to address whether the effect of enalapril is merely related to cardiac unloading or may reflect other properties of ACE inhibitors. Whatever the case, the observation that enalapril restored to normal the overall cardiac adaptations to increased preload in DCM patients may further account for the favorable influence of this compound in the mild or early stages of heart failure.19 20
Finally, our study supports the usefulness of the assessment of the cardiac adaptations to blood volume manipulations in heart failure. Clinical detection of ventricular dysfunction and evaluation of cardiac reserve mechanisms in heart failure are currently based on the assessment of the responses to physical exercise. However, this may be insufficient, especially in the mild or early stages of heart failure. Furthermore, the use of exercise may not be adequate to reflect the influence of physiological changes in blood volume (ie, meals, recumbency, immersion, etc) on cardiac function that may be important in heart failure. In fact, in our study, acute volume overload revealed significant impairment of preload recruitment in patients with compensated left ventricular dysfunction and relatively preserved response to physical exercise.
Selected Abbreviations and Acronyms
|CHF||=||congestive heart failure|
|NYHA||=||New York Heart Association|
This study was supported in part by Italian National Research Council grant 91.00128.PF41 (targeted project “Prevention and Control of Disease Factors”: subproject “Cardiomyopathies”).
- Received December 29, 1994.
- Revision received June 5, 1995.
- Accepted June 8, 1995.
- Copyright © 1995 by American Heart Association
Weber KT, Kinasewitz GT, Janicki JS, Fishman AP. Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation. 1982;65:1213-1223.
Braunwald E, Plautch WH, Morrow JR. A method for the detection and quantification of impaired sodium excretion: results of an oral sodium tolerance test in normal subjects and in patients with heart disease. Circulation. 1965;32(suppl 8):223-231.
Ross J Jr, Gault JH, Mason DT, Linhart JW, Braunwald E. Left ventricular performance during muscular exercise in patients with and without cardiac dysfunction. Circulation. 1966;34:597-608.
Higginbotham MB, Morris KG, Williams RS, McHale PA, Coleman RE, Cobb FR. Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ Res. 1986;58:281-291.
Poliner LR, Dehmer GJ, Lewis SE, Parkey RW, Bloomqvist CG, Willerson JT. Left ventricular performance in normal subjects: a comparison of the responses to exercise in the upright and supine positions. Circulation. 1980;62:528-534.
Benge W, Litchfield RL, Marcus ML. Exercise capacity in patients with severe left ventricular dysfunction. Circulation. 1980;61:955-959.
Konstam MA, Kronenberg MW, Udelson JE, Kinan D, Metherall J, Dolan N, Edens T, Hove D, Kilcoyne L, Benedict C, Youngblood M, Barrett J, Yusuf S, for the SOLVD Investigators. Effectiveness of preload reserve as a determinant of clinical status in patients with left ventricular systolic dysfunction. Am J Cardiol. 1992;69:1591-1595.
Volpe M, Tritto C, DeLuca N, Mele AF, Lembo G, Rubattu S, Romano M, deCampora P, Enea I, Ricciardelli B, Trimarco B, Condorelli M. Failure of atrial natriuretic factor to increase with saline load in patients with dilated cardiomyopathy and mild heart failure. J Clin Invest. 1991;88:1481-1489.
Volpe M, Tritto C, DeLuca N, Rubattu S, Mele AF, Lembo G, Enea I, deCampora P, Rendina V, Romano M, Trimarco B, Condorelli M. Angiotensin converting enzyme inhibition restores cardiac and hormonal responses to volume overload in patients with dilated cardiomyopathy and mild heart failure. Circulation. 1992;86:1800-1809.
Imbriaco M, Cuocolo A, Pace L, Nappi A, Nicolai E, Cardei F, Morisco C, Romano M, Salvatore M. Ambulatory monitoring of left ventricular function during cardiopulmonary exercise test in normal sedentary subjects. J Nucl Med. In press.
Zaret BL, Jain D. Continuous monitoring of left ventricular function with miniaturized nonimaging detectors. In: Zaret BL, Beller GA, eds. Nuclear Cardiology: State of the Art and Future Directions. St Louis, Mo: Mosby-Year Book Inc; 1993:137-145.
Kayden DS, Remetz MS, Cabin HS, Deckelbaum LI, Cleman MW, Wackers FJ, Zaret BL. Validation of continuous radionuclide left ventricular functioning monitoring in detecting silent myocardial ischemia during balloon angioplasty of the left anterior descending coronary artery. Am J Cardiol. 1991;67:1339-1343.
Konstam MA, Kronenberg HW, Rousseau MF, Udelson JE, Melin J, Stewart D, Dolan N, Edens TR, Ahn S, Kinan D, Howe DM, Kilcoyne L, Metherall J, Benedict C, Yusuf F, Pouleur H, for the SOLVD Investigators. Effects of angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dilatation in patients with asymptomatic systolic dysfunction. Circulation. 1993;88:2277-2283.
Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang C, Kubo SH, Rudin-Toretsky E, Yusuf S, for the SOLVD investigators. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure: a substudy of the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation. 1990;82:1724-1729.
Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Blood Vessels. Boston, Mass: Little Brown & Co; 1973:286.
Pace L, Cuocolo A, di Mangoni S, Stefano ML, Nappi A, Nicolai E, Imbriaco M, Trimarco B, Salvatore M. Left ventricular systolic and diastolic function measurements using an ambulatory radionuclide monitor: effects of different time averaging on accuracy. J Nucl Med. 1993;34:1602-1606.
Kirkendall MW, Burton MC, Epstein FM, Freis ED. Recommendations for human blood pressure determination by sphygmomanometers. Circulation. 1967;36:980-986.
Biollaz J, Burnier M, Turini GA, Brunner DB, Porchet M, Gomez HJ, Jones KH, Ferber F, Abrams WB, Gavras H, Brunner HR. Three new long acting converting enzyme inhibitors: relationship between plasma converting-enzyme activity and response to angiotensin I. Clin Pharmacol Ther. 1981;29:665-670.
Folland ED, Parisi AF, Moghihan BS, Joney DR, Feldman CL, Tow DE. Assessment of left ventricular ejection fraction and volumes by real-time, two-dimensional echocardiography. Circulation. 1979;60:760-771.
Imbriaco M, Cuocolo A, Pace L, Nappi A, Nicolai E, Maurea S, Salvatore M. Repeatability of haemodynamic responses to cardiac stimulations by ambulatory monitoring of left ventricular function. J Nucl Biol Med. 1993;37:238-244.
Volpe M, Lembo G, DeLuca N, Lamenza F, Indolfi C, Condorelli GL, Trimarco B. Converting enzyme inhibition prevents the effects of atrial natriuretic factor on arterial baroreflexes. Circulation. 1990;82:1214-1221.
Wilkinson L, Hill MA, Welna JP, Birkenbeuel GK. SYSTAT for Windows: Statistics, Version 5 Edition. Evanston, Ill: SYSTAT Inc; 1992.
Volpe M, Tritto C, DeLuca N, Rubattu S, Rao MAE, Lamenza F, Mirante A, Enea I, Rendina V, Mele AF, Trimarco B, Condorelli M. Abnormalities of sodium handling and of cardiovascular adaptations during high salt diet in patients with mild heart failure. Circulation. 1993;88:1602-1627.
Gaasch WH, Carroll JD, Blaustein AS, Bing OH. Myocardial relaxation: effects of preload on the time course of isovolumetric relaxation. Circulation. 1986;73:1037-1041.
Ludbrook PA, Byrne JD, McKnight RC. Influence of right ventricular hemodynamics on left ventricular diastolic pressure-volume relations in man. Circulation. 1979;59:21-31.
Carroll JD, Land RM, Neumann AL, Borow KM, Rajfer SI. The differential effects of positive inotropic and vasodilator therapy on diastolic properties in patients with congestive cardiomyopathy. Circulation. 1986;74:815-825.
Konstam MA, Kronenberg MW, Udelson JE, Metherall J, Dolan N, Edens TR, Howe DM, Yusuf S, Youngblood M, Toltsis H, and the SOLVD Investigators. Effect of acute angiotensin converting enzyme inhibition on left ventricular filling in patients with congestive heart failure: relation to right ventricular volumes. Circulation. 1990;81(suppl III):III-115-III-122.