Plasma Volume and Its Regulatory Factors in Congestive Heart Failure After Implantation of Long-term Left Ventricular Assist Devices
Background Congestive heart failure is associated with blood volume expansion caused by stimulation of the renin-aldosterone system and arginine vasopressin. The use of left ventricular assist devices as bridges to heart transplantation has improved the survival of patients during this critical period. In studying heart failure physiology on support devices, we hypothesized that improvement of cardiac function by a left ventricular assist device is associated with normalization of volume load secondary to normalization of its regulatory substances.
Methods and Results We studied 15 patients (13 men, 2 women; age, 51±8 years) with end-stage heart failure who were cardiac transplant candidates eligible for HeartMate implantation. We measured plasma volume and plasma levels of atrial natriuretic peptide, aldosterone, renin, and arginine vasopressin sequentially before HeartMate implantation (baseline), after HeartMate implantation (weeks 4 and 8), and after transplantation. Baseline plasma volume was 123±20% of normal; it was 122±22% at week 4 and decreased to 115±14% at week 8. Atrial natriuretic peptide was 359±380 pg/mL at baseline, 245±175 pg/mL at week 4, and 151±66 pg/mL at week 8. Plasma aldosterone fell from 68±59 ng/dL at baseline to 17±16 ng/dL at week 4 (P<.05 versus baseline) and was 32±50 ng/dL at week 8. Plasma renin activity decreased from 80±88 ng/dL at baseline to 11±12 ng/dL at week 4 and was 16±38 ng/dL at week 8 (both P<.05 versus baseline). Arginine vasopressin fell from 5.0±4.8 fmol/mL at baseline to 1.1±0.7 fmol/mL at week 4 and 1.2±0.8 fmol/mL at week 8 (both P<.05 versus baseline).
Conclusions The reduction of plasma renin activity, plasma aldosterone, and arginine vasopressin occurred earlier than the reduction of plasma volume and atrial natriuretic peptide after HeartMate implantation, possibly because of decreased pulmonary congestion and improved renal perfusion. The reduction of atrial natriuretic peptide cannot be responsible for the lack of adequate decrease of plasma volume; its reduction can be taken as a marker of improved cardiac pump function and decreased atrial stretch.
Congestive heart failure is associated with blood volume expansion that by itself increases the hemodynamic burden on the heart. Elevation of plasma volume in congestive heart failure has been attributed to stimulation of the renin-aldosterone system and AVP.1 2 3 4 The elevation of ANP in heart failure also has been well described.5 6
The use of ventricular assist devices, particularly the long-term implantable LVAD, has enhanced the survival of heart failure patients when used as a bridge to cardiac transplantation. Studies have been ongoing to elucidate the effects of support devices on heart failure physiology as the role of support devices in end-stage heart failure grows, with permanently implantable LVADs on the horizon. The aim of this study was to evaluate the effect of LVADs on plasma volume and its regulatory substances. The value of plasma volume and its regulatory factors as predictors of prognosis in heart failure patients awaiting LVAD implantation also was assessed.
The HeartMate device (Thermo Cardiosystems, Inc) was implanted in each patient through a median sternotomy incision while the patient was on cardiopulmonary bypass.7 The device was placed in a pocket in the left upper abdominal wall. The inflow conduit was inserted into the left ventricular cavity after excision of a core of left ventricular apex, while the outflow conduit was anastomosed to the ascending aorta. Inflow and outflow tissue valves were used. With the HeartMate, blood flowed from the left ventricle through the inflow cannula into the pump and then was ejected into the ascending aorta. Because the HeartMate very efficiently unloads the left ventricle, the patient’s aortic valve usually does not open during systole. Air is vented from the device as cardiopulmonary bypass is weaned, and LVAD operation is begun.
The 15 patients enrolled in the study were candidates for HeartMate devices and had plasma volume and laboratory data. The study group consisted of 13 men and 2 women with a mean age of 51±8 years. All were in cardiogenic shock (mean cardiac index, 1.7±0.4 L·min−1·m−1) and were approved for cardiac transplantation. The cause of the underlying heart disease was ischemic cardiomyopathy in 11 patients, dilated cardiomyopathy in 2, infiltrative cardiomyopathy in 1, and hypertensive cardiomyopathy in 1. All patients gave consent in accordance with the Institutional Review Board at the Cleveland Clinic.
Timing of Samplings
Venous samplings of ANP, PRA, AVP, and PA were drawn from each patient at baseline (within 24 hours before HeartMate insertion), at 1 and 2 months after HeartMate implantation, and 1 month after heart transplantation. Plasma volume, red cell mass, and hematocrit were measured at the same intervals as the regulatory factors. All patients who were able to maintain oral intake were on low-sodium (2 g/d) diets before and after implantation.
Pulmonary artery catheters were in place in all patients at baseline, but after 1 month of HeartMate support, they were discontinued in many patients. Cardiac output and right ventricle pressures were recorded at baseline before HeartMate insertion and at the time of explantation or cardiac transplantation in those who survived to explantation.
The echocardiograms were performed by transesophageal echocardiography at implantation and explantation with imaging systems by Hewlett Packard model SONOS OR or SONOS 1500. Two-dimensional transesophageal echocardiograms were used to measure the distance (diameter) between the lateral atrial wall and atrial septum in systole in the basal four-chamber transesophageal view as an indication of atrial size.
Before HeartMate insertion, all patients were on standard anticongestive medications consisting of digoxin, an angiotensin-converting enzyme inhibitor, and diuretics. After HeartMate implantation, only 1 patient received an angiotensin-converting enzyme inhibitor (captopril) throughout the study. No patients were on digoxin throughout the study. Use of these medications was minimal because of the hemodynamic and clinical improvement in heart failure effected by the LVAD alone.
Seven patients did not receive diuretics. The other 8 patients did receive diuretics; Table 1⇓ gives their regimens.
Plasma Volume and Red Cell Mass Measurements
Plasma volume was measured with 10 mCi 125I–radioiodinated serum albumin IV with a 10-minute equilibration period.8 Total blood volume was calculated from plasma volume and simultaneously measured venous hematocrit. Values were calculated as percent of normal for sex to allow averaging of data obtained from men and women. Normal values for our laboratory are 29.4±0.8 mL/cm height for men and 23.7±0.5 mL/cm height for women.
Regulatory Factor Measurements
A short 18- or 20-gauge intravenous cannula connected to a three-way stopcock was used to obtain plasma venous samplings. The catheter was filled with diluted heparinized saline solution, with samplings performed after 30 minutes of supine rest. A total of 64 mL blood was obtained to perform all the hormonal assays per patient sampling. Blood for PRA (10 mL) was drawn into a tube containing liquid potassium and EGTA. After inversion of the tubes several times for mixing, the sample was centrifuged within 1 hour at 4°C and 2500 rpm for 15 minutes. Plasma AVP and ANP samples were placed in prechilled EGTA tubes, centrifuged, and stored as described. All samples were transported on ice for analysis to the Endocrine/Hypertension Research Laboratory, Research Institute, the Cleveland Clinic.
PRA was measured by RIA of generated angiotensin I as previously described.9 Values in 25 normal supine subjects averaged 1.2±0.84 ng·mL−1·h−1 and ranged from 0.6 to 2.6 ng·mL−1·h−1.
Plasma AVP was assayed by RIA according to the methods of Crofton et al.10 Intraassay and interassay coefficients of variation for plasma AVP were 5% and 8%, respectively. Samples with values below the detectability limit of the assay (<0.5 pg/mL) were assigned a value of 0.4 pg/mL. Normal values ranged from 0.4 to 3.6 pg/mL.
Plasma aldosterone levels were assayed by RIA. The technique used was described by Bravo et al.11
Plasma ANP was measured by an RIA technique developed in the laboratory of one of the authors (E.L.B.). The RIA is a 3-day assay involving prior plasma extraction with Bon Elut C-18 columns and a 24-hour preincubation of standards, controls, and samples with antibody at 4°C. Separation of bound from free fractions was achieved by second antibody and normal rabbit serum. The sensitivity of the assay is 12 pg/mL. The intraassay and interassay coefficients of variation were 6.5% and 14%, respectively. Normal control subjects (n=18) had plasma concentrations of 30.4±2.5 pg/mL (mean±SE) on normal salt intake, which decreased to 16.4±1.5 pg/mL on salt deprivation and increased to 55.0±6.7 pg/mL on a high-salt diet.
Laboratory and hemodynamic data are expressed as mean±SD. Comparisons between any two groups were done with Student’s t test. For Table 2⇓, in which three groups are compared, a repeated measures ANOVA model was used.
Correlations among laboratory, hemodynamic, and echocardiographic variables were assessed with the Spearman or Pearson test. A value of P<.05 was considered significant.
Of the 15 study patients eligible for HeartMate devices, 4 died while on HeartMate support of persistent right ventricle dysfunction with multiple organ failure. The remaining 11 received LVADs and subsequently underwent cardiac transplantation.
Plasma Volume and Regulatory Factors
Baseline plasma volume was 123±20% of normal; it was 122±22% at week 4 and decreased to 115±14% at week 8. ANP was 359±380 pg/mL at baseline, 245±175 pg/mL at week 4, and 151±66 pg/mL at week 8. PA fell from 68±59 ng/dL at baseline to 17±16 ng/dL at week 4 (P<.05 versus baseline) and was 32±50 ng/dL at week 8. PRA decreased from 80±88 ng/dL at baseline to 11±12 ng/dL at week 4 and was 16±38 ng/dL at week 8 (both P<.05 versus baseline). AVP fell from 5.0±4.8 fmol/mL at baseline to 1.1±0.7 fmol/mL at week 4 and was 1.2±0.8 fmol/mL at week 8 (both P<.05 versus baseline).
After cardiac transplantation, the decreases in plasma volume and regulatory substances that had occurred after LVAD implantation were maintained, with no significant changes in these values. Table 3⇓ gives these data.
Plasma volume and regulatory factors were compared between survivors and nonsurvivors. One significant parameter emerged in differentiation between the two groups. PRA was markedly higher in the 4 nonsurvivors than in the survivors (182±122 versus 43±27 ng/dL, respectively; P=.005).
The surviving patients exhibited significant hemodynamic improvement on LVAD support, with an increase in mean cardiac index of 1.7±0.4 L · min−1 · m−1 at baseline to 3.1±1.0 L · min−1 · m−1 at explantation (P=.001). Mean left atrial pressure decreased from 24.6±8.7 mm Hg at implantation to 8.5±4.6 mm Hg at explantation (P<.001); mean right atrial pressure also fell from 20.7±7.0 to 10.6±4.1 mm Hg, respectively (P<.001; Table 4⇓).
Of the patients who received HeartMate devices, baseline and explantation echocardiograms were available in 8. In this group, mean left atrial diameter decreased from 4.9±0.5 to 3.6±0.5 cm (P<.0004). Mean right atrial diameter decreased from 4.8±1.1 to 3.9±0.6 cm at explantation (P=.07).
Normal atrial dimensions for transesophageal echocardiograms are comparable to those assessed transthoracically.12 13 Normal right atrial dimension by transesophageal echocardiography in young adults is 2.4±0.4 cm; normal left atrial dimension, 2.4±0.5 cm.13
Correlations among all the regulatory substances, hemodynamic, and echocardiographic variables were assessed at baseline and at 8 weeks after LVAD implantation. Three statistically significant correlations were found at baseline: (1) plasma volume correlated with right atrial pressure (r=.82, P=.01), right atrial pressure at LVAD implantation correlated with echocardiographic right atrial diameter (r=.92, P=.009), and PRA correlated with PA (r=.69, P=.002).
At 8 weeks after HeartMate implantation, plasma volume no longer correlated with right atrial pressure (r=.31, P=.35). The only significant correlation at 8 weeks was between left atrial pressure and mean pulmonary arterial pressure (r=.66, P=.04).
Marked hemodynamic improvement was seen after implantation of the long-term LVAD, with a significant increase in cardiac index and decreases in left and right atrial and pulmonary arterial pressures. These beneficial alterations in hemodynamics reflect the effective unloading of the left ventricle by the LVAD. In addition to these hemodynamic improvements on long-term LVAD support, other beneficial cardiac effects have been described, including a decrease in histological parameters of acute myocyte damage14 and downregulation of neurohormones such as norepinephrine and epinephrine.15
Along with the hemodynamic improvement on LVAD support, plasma volume decreased somewhat. There are several possible reasons why the plasma volume tends to decrease. First, the increased cardiac output augments renal perfusion16 and accordingly leads to excretion of excess volume. We previously described physiological improvement secondary to augmented left-side output, wherein renal function in patients on HeartMate support normalizes in those who survive to undergo cardiac transplantation.17 Second, the decrease in atrial and pulmonary pressures on LVAD support can lead to the decrease in the regulatory substances (PRA, PA, and AVP), leading to decreased plasma volume. As seen earlier, during congestive heart failure at baseline, plasma volume correlates with right atrial pressure. Indeed, the reductions in PRA, PA, and AVP occur earlier than the reduction in plasma volume, suggesting that the decrease in these factors leads to a subsequent decrease in plasma volume.
Of note, 8 patients received diuretics during the study. It has been well documented that diuretic use will elevate PRA and PA levels.18 19 At baseline, during congestive heart failure, not surprisingly PA and PRA significantly correlate with each other and are elevated, reflecting the secondary hyperaldosterone state of heart failure. Despite subsequent diuretic use, however, these regulatory factors still decrease in LVAD support, indicating that the beneficial hemodynamic effect of the LVAD overrides even that of diuretic use on PRA and PA levels.
Follow-up measurement of plasma volume and hormones, obtained 1 month after cardiac transplantation, reveals no major change from the levels while patients are on HeartMate support (Table 3⇑). The improvement in volume status and its regulators on ventricular support is maintained after transplantation. Of note, plasma volume does not change significantly after transplantation, although all patients receive a transfusion at the time of transplantation. This probably reflects maintained hemodynamic improvement with the donor hearts.
The ANP level decreases, but not to the degree as the other regulatory factors. Therefore, the persistently elevated ANP after LVAD implantation does not explain the decrease in plasma volume. Rather, the ANP reduction can be taken as a marker of improved cardiac pump function with somewhat decreased atrial stretch. There are several possible reasons why ANP fails to decrease more on LVAD support.20 21 First, the hemodynamic data show that both mean right and left atrial pressures significantly decrease on HeartMate support. The decrease in right-side (pulmonary artery) pressures correlates with the decrease in left atrial pressures. Nonetheless, the mean right atrial pressure remains somewhat elevated and actually exceeds left atrial pressure on LVAD support. This probably reflects the effect of the LVAD selectively unloading the left side of the heart. Second, the echocardiographic data similarly reveal a decrease in the mean diameters of the atria on LVAD support, with more of a decrease in the left than in the right. This preferential decrease in left over right atrial dimension is accompanied by an alteration in atrial geometry: actual bowing of the interatrial septum is seen in the patients. Pulmonary vascular resistance decreases during LVAD support, but not completely; therefore, the right ventricle still ejects against elevated afterload (Table 4⇑). Similarly, right ventricular function shows improvements in ejection fraction and volume, but again the right ventricular function does not totally normalize.17 This helps explain why right atrial dimension decreases echocardiographically, but not to completely normal values. Therefore, it can be postulated that persistent right atrial stretch is responsible for a persistent elevation in ANP. Third, the left ventricle itself has previously been shown to be a source of ANP.22 Finally, on a speculative basis, it is conceivable that the LVAD may actually stimulate ANP release.
Red cell mass decreased after HeartMate implantation but later corrected somewhat after cardiac transplantation. The lower red cell mass in patients while on LVAD support is probably due to a combination of blood loss, hemolysis, and chronic illness. Of note, routine anticoagulation is not necessary with the HeartMate device because of the known low incidence of thromboembolic complications.7
In terms of prognosis, markedly elevated PRA is significantly associated with death after HeartMate implantation. This high PRA is probably a manifestation of the extreme activation of the renin-angiotensin system in those who succumb to persistent right ventricle failure, the major cause of death in this population. Parameters of right ventricle function, such as right atrial dimension and pressure, were not available for assessment in follow-up owing to the untimely deaths in this subset before explantation or transplantation.
On implantable LVAD support, there is a pronounced improvement in hemodynamics that is accompanied by a decrease in plasma volume and its regulatory factors. Although plasma volume decreases, this decrease does not reach statistical significance and, even at 8 weeks, does not fully normalize. ANP similarly decreases, but not significantly, and remains at least twice the normal level at 8 weeks. Despite normal left-side cardiac output and renal perfusion, plasma volume status improves somewhat but remains mildly expanded in the face of persistently elevated ANP, suggesting that the mechanism for the persistent increase in plasma volume may be related to persistent right ventricle failure. Alternatively, plasma volume may simply lag behind other physiological and hemodynamic changes.
This study documents excellent improvement in left-side cardiac hemodynamics on long-term LVAD support. Right ventricle function improves, but there is evidence of residual impairment of right ventricle physiology with elevated right atrial dimensions, right atrial pressures, pulmonary vascular resistance, ANP levels, and plasma volume.
Right ventricle failure (usually associated with multiple organ failure) is the most common cause of death after LVAD implantation.17 Persistent, extreme elevation of PRA appears to be associated with a grave prognosis, reflecting marked activation of the renin-angiotensin axis. In this study, we have identified evidence of persistent right ventricle dysfunction, albeit not fatal, in most patients. As the indications for LVAD implantation expand, more patients with various degrees of right ventricle recovery probably will receive implantations. Therefore, continued investigation of the effects of LVADs on right ventricle physiology is crucial as the role of permanently implantable LVADs as an alternative to cardiac transplantation approaches in the near future.
Selected Abbreviations and Acronyms
|ANP||=||atrial natriuretic peptide|
|LVAD||=||left ventricular assist device|
|PRA||=||plasma renin activity|
The assays were funded by the Cleveland Clinic Department of Cardiothoracic Surgery. HeartMate implantable LVAD is manufactured by Thermo Cardiosystems Inc.
Reprint requests to Karen B. James, MD, the Cleveland Clinic Foundation, Department of Cardiology, F25, 9500 Euclid Ave, Cleveland, OH 44195.
- Received June 5, 1995.
- Revision received September 25, 1995.
- Accepted November 3, 1995.
- Copyright © 1996 by American Heart Association
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