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J Am Coll Cardiol, 2006; 47:2528-2535, doi:10.1016/j.jacc.2006.03.022 (Published online 24 May 2006).
© 2006 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: CONGENITAL HEART DISEASE

Cardiac Rest and Reserve Function in Patients With Fontan Circulation

Hideaki Senzaki, MD*, Satoshi Masutani, MD, Hirotaka Ishido, MD, Mio Taketazu, MD, Toshiki Kobayashi, MD, Nozomu Sasaki, MD, Haruhiko Asano, MD, Toshiyuki Katogi, MD, Shunei Kyo, MD and Yuji Yokote, MD

Department of Pediatric Cardiology and Cardiovascular Surgery, Saitama Medical School Hospital, Saitama, Japan

Manuscript received October 8, 2005; revised manuscript received January 30, 2006, accepted February 7, 2006.

* Reprint requests and correspondence: Dr. Hideaki Senzaki, Division of Pediatric Cardiology, Saitama Heart Institutes, Saitama Medical School Hospital, 38 Morohongo, Moroyama, Iruma-Gun, Saitama, 350-0495 Japan. (Email: hsenzaki{at}saitama-med.ac.jp).


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: In the present study, we systematically tested cardiac rest and reserve function in patients with Fontan physiology to check for inherent limitations of this circulation.

BACKGROUND: Details of the mechanisms of cardiac performance that could account for adverse outcome after Fontan surgery are not well understood.

METHODS: The subjects were 17 Fontan patients with good functional status (Fontan group) and 20 patients with normal two-ventricle circulation (control group). We examined baseline ventricular contractility, diastolic function, and loading factors, and examined changes in those parameters in response to increased heart rate (HR) due to atrial pacing and in response to beta-adrenergic stimulation, using ventricular pressure-area relationships during preload reduction.

RESULTS: At baseline, the Fontan patients exhibited minimal abnormality of cardiac properties, but the significant increase in afterload resulted in decreased cardiac index. In addition, Fontan circulation was associated with limited inotropic response and worsening of diastolic filling with increased HR, leading to decreased systolic pressure and elevation of central venous pressure at higher HRs (p < 0.05 vs. control). Furthermore, beta-adrenergic reserve was markedly decreased in the Fontan group, compared with controls, owing to limited preload reserve rather than limited contractile reserve.

CONCLUSIONS: Because normal ventricular-vascular interaction and augmentation of cardiac performance during increased HR and adrenergic stimulation are important for maintaining cardiac output and exercise capacity, the present results may have important implications for the mechanisms underlying adverse outcome after Fontan surgery. Thus, improvement of long-term prognosis of patients after Fontan surgery requires the development of medical interventions that can overcome such limitations inherent in Fontan circulation.

Abbreviations and Acronyms
  CI = cardiac index
  Ea = effective arterial elastance
  EDAI = end-diastolic area index
  EDP = end-diastolic pressure
  EDPAR = end-diastolic pressure-area relation
  Ees = end-systolic elastance
  ESP = end-systolic pressure
  FS = fractional shortening
  HR = heart rate
  IVC = inferior vena caval
  SAI = stroke area index

Although the Fontan operation has greatly contributed to the improvement of mortality in patients with a single ventricle (1,2), recent reports have emphasized the continuing risk of late failure and poor functional outcome in some long-term survivors (2,3). Decreased exercise tolerance with abnormal chronotropic response has also been clearly observed in patients after the Fontan procedure (4–6). Although these results strongly suggest fundamental limitations inherent in Fontan physiology, details of the mechanisms of cardiac performance that could account for such adverse outcome are not well understood. This is partly because previous evaluations of cardiac performance of Fontan circulation were too often limited by reliance on measurements with complex interdependence between cardiac properties and loading factors. Furthermore, although it is well established that cardiac reserve function in response to increased heart rate (HR) and beta-adrenergic stimulation is an important determinant of cardiac performance, and is closely related to exercise capacity and functional status in several heart diseases (7,8), there has never been a systematic test of those relationships in patients with Fontan physiology.

In the present study, to check for mechanisms of cardiac performance underlying reported adverse outcomes of Fontan surgery, we examined cardiac rest and reserve function in patients with Fontan physiology, using ventricular pressure-area (P-A) analysis that allows separate quantification of ventricular chamber and loading properties (9,10).


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Patients.   We studied 37 subjects: 17 patients with Fontan circulation (Fontan group; mean age 6.3 ± 1.1 years), and 20 patients who were considered to have normal two-ventricle circulation (control group; mean age 6.6 ± 1.1 years). For the Fontan group, anatomic diagnoses and palliations performed before Fontan surgery are summarized in Table 1. All Fontan patients were asymptomatic and in New York Heart Association functional class I. None of the Fontan patients had significant atrioventricular valve regurgitation or pulmonary artery stenosis. All Fontan patients had undergone total cavopulmonary connection surgery with an intra-atrial lateral tunnel. In 5 of the Fontan patients, there was a shunt flow through a surgically created fenestration; these patients were examined with the fenestration temporarily occluded by a balloon-tipped catheter. Because the shunt flow in these five patients was minimal, there was no evidence of erythrocytosis and no marked rise in central venous pressure (CVP) (range 0 to 1.2 mm Hg) during the occlusion. All control patients had a small subpulmonic ventricular septal defect (calculated pulmonary-to-systemic flow ratio 1.0), which can cause aortic valve prolapse and resultant aortic regurgitation (11). Accordingly, all control patients underwent cardiac catheterization to check for deformity of aortic valves and aortic regurgitation; cardiac catheterization with angiography is a routine practice at our institution. There was no significant regurgitation in any of the control subjects. The same anesthesia protocol was used for all subjects (premedication with intramascular pethidine and atropine, and sedation with continuous infusion of sodium thiamylal during catheterization). Written informed consent was obtained from the parents of all patients, and the procedures were approved by the Committee on Clinical Investigation of Saitama Medical School Hospital.


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  		Table 1. Patient Characteristics of Fontan group
 
Procedures.   After routine cardiac catheterization and before angioventriculography, ventricular P-A relations were constructed by simultaneously measuring ventricular chamber pressure and area both at rest and during preloads varied by transient inferior vena caval (IVC) balloon obstruction. Details of this procedure have previously been reported (10,12,13). Briefly, ventricular pressure was measured with a high-fidelity pressure transducer mounted on a 0.014-inch diameter guidewire (Radi Medical Systems, Inc., Wilmington, Massachusetts) in a 4- or 5-F pigtail catheter. Instantaneous ventricular cavity area was measured using an automated border detection echocardiographic system (Sonos 5500, Hewlett-Packard, Agilent Technologies, Inc., Palo Alto, California). Careful adjustments for overall transmission, time gain compensation, and lateral gain controls provided a stable real-time area waveform throughout the study procedures. Transthoracic two-dimensional images were recorded from the midventricular short-axis plane, using the papillary muscle as an anatomic landmark. Right and left ventricular areas were measured for patients with a functional single ventricle. Changes in stroke area during IVC occlusion closely correlated with changes in stroke volume simultaneously measured using a catheter-mounted electromagnetic flow probe (Millar Instruments, Houston, Texas) (r = 0.89 ± 0.08; standard error of estimate = 7 ± 4%; with a regression slope of 0.92 ± 0.14), indicating that the method is valid for area measurements.

After baseline hemodynamic measurements and P-A analysis, we examined hemodynamic responses to increased HR by performing atrial pacing. Pacing rates were increased by 20/min, from the baseline HR to a maximum of 180/min. After the pacing protocol, to examine hemodynamic responses to beta-adrenergic stimulation, dobutamine was intravenously administered (5 µg/kg/min) and hemodynamic measurements and P-A analysis repeated.

Data analysis.   Three to five consecutive steady-state beats during expiration were signal-averaged and used to calculate end-diastolic pressure (EDP) and end-systolic pressure (ESP) and end-diastolic area (EDA) and end-systolic area (ESA), stroke area, fractional shortening (FS), peak rate of ventricular pressure rise (dP/dtmax), time constant of ventricular relaxation ({tau}), and the effective arterial elastance (Ea), which is a lumped measure of ventricular afterload (10). Area data were normalized to body surface area, and were expressed as end-diastolic area index (EDAI), end-systolic area index (ESAI), and stroke area index (SAI). Cardiac index (CI) was obtained by multiplying SAI by HR, and Ea was calculated as dividing ESP by SAI. The value {tau} was calculated using a logistic fit, which provides a more stable parameter than monoexponential models (14). Ventricular relaxation was also assessed by calculating the preload-adjusted peak filling rate (PFR/EDAI) during early rapid filling. The preload-adjusted maximal ventricular power (PWRmax), which is reportedly a load-independent measure of contractility, was calculated as previously described (15).

Data measured during preload varied by transient IVC occlusion were used to calculate the slope (end-systolic elastance [Ees]) of the end-systolic pressure-area relation (ESPAR), the slope of the relation between stroke area work and EDAI (preload-recruitable stroke area [Msw]), and the end-diastolic pressure-area relation (EDPAR). The Ees and Msw provide load-insensitive measures of contractility (10,15,16). The EDPAR was fitted to a monoexponential function (P = P0 + {alpha}[eßEDAI – 1]), yielding passive diastolic chamber stiffness (ß) (16,17).

Statistical analysis.   All values were expressed as mean ± SEM, and comparisons between the two groups were made using the unpaired t test. The effects of HR on each parameter were calculated by performing repeated-measures analysis of variance, with post hoc testing using the Dunnett multiple comparisons test. Multiple regression analysis including group factor was performed to test for independent effects of group classification (Fontan circulation) on the HR dependence of each parameter, providing both an offset (i.e., Fontan circulation alters mean value of parameter but does not alter rate dependence) and an interaction effect (Fontan circulation alters HR dependence). Comparisons between data obtained before and after the dobutamine infusion were made using a paired t test. A p value of <0.05 was considered to indicate statistical significance. All statistical analyses were performed using Systat version 6.0 (Systat Software, Inc., Point Richmond, California).


   Results
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 Abstract
 Methods
 Results
Discussion
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Hemodynamics, vascular load, and ventricular function at baseline.   Baseline data for each group are summarized in Table 2. Consistent with previous reports (5,6,18), the Fontan group had significantly lower CI and significantly higher CVP than the controls (both p < 0.01). In addition, the Fontan group had lower FS than the control group (p < 0.01). However, there was little difference in baseline values of more heart-specific indexes of ventricular contractility (Ees, Msw, PWRmax/EDAI3/2, and dP/dtmax/EDAI) between the Fontan group and the control group, indicating that Fontan patients with good functional status have normal ventricular contractility. On the other hand, Ea was significantly higher in the Fontan group than in the control group; consequently, the ventricular-vascular coupling ratio (Ees/Ea) was significantly lower in the Fontan group than in the control group. Because the two groups had similar preload conditions (EDAI), these results indicate that increased afterload is a fundamental feature of baseline hemodynamics of Fontan circulation, and that it is responsible for the decreased CI and FS of Fontan circulation. In addition, ventricular relaxation (represented by {tau} and PFR/EDAI) was significantly delayed in the Fontan group compared with the control group. In contrast, there was little difference in diastolic passive chamber stiffness (ß) between the Fontan group and the control group, and the two groups also had comparable values of net chamber filling (similar EDP at similar EDAI). Thus, delayed relaxation is also a feature of Fontan physiology at rest, but its effect on overall diastolic filling is minimal.


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  		Table 2. Baseline Hemodynamic Data of Fontan and Control Subjects
 
The P-A relations displayed in Figure 1 clearly demonstrate the aforementioned differences in resting cardiovascular functions and interaction between the two groups. Whereas the slope of ESPAR (Ees) of the Fontan group patient is similar to that of the control subject, the slope indicating Ea of the Fontan group patient is much steeper (increased afterload) than that of the control subject at similar preloads (EDAI), resulting in decreased SAI of the Fontan group patient, compared with the control subject. The Fontan group patient and the control subject had almost identical EDPARs, indicating normal chamber diastolic stiffness in the Fontan group patient.


Figure 1
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  		Figure 1 Pressure-area loops and relations in representative patients from control (left) and Fontan (right) groups.

 
Responses to increased heart rate by pacing.   Figure 2 shows mean changes in hemodynamic (Fig. 2A), systolic (Fig. 2B), and diastolic (Fig. 2C) parameters in response to pacing in each group, and Table 3 shows the results of multiple regression analysis used to test for effects of group classification on the pacing response. Pacing significantly reduced SAI and ESP in both groups (p < 0.01), but the magnitude of these changes were significantly greater in the Fontan group than in the control group. The CVP increased progressively in the Fontan group, whereas there was no significant change in the control group.


Figure 2
Figure 2
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  		Figure 2 Mean changes in hemodynamic (A), systolic (B), and diastolic (C) parameters in response to pacing in each group. Statistically significant differences revealed by repeated measures analysis of variance are indicated by #, and those revealed by Dunnett multiple comparisons are indicated by *. Filled squares = control; open triangles = Fontan.

 

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  		Table 3. Effect of Patient Group on Heart Rate Dependence of Cardiac and Hemodynamic Parameters
 
The Ees and other contractile indices showed a markedly weaker response with pacing in the Fontan group than in the control group (Fig. 2B, Table 3), indicating that Fontan circulation has an inherently limited cardiac contractile reserve in response to increased HR.

In addition to their abnormal systolic reserve, Fontan patients also had an abnormal diastolic response. In the control subjects, EDP significantly and progressively decreased with pacing (p < 0.01). In the Fontan group, the decrease in EDP with incremental pacing rate was less marked than in the control group, and EDP tended to increase at faster rates (p < 0.05 vs. control for interaction effect). Interestingly, although at baseline the Fontan group exhibited more prolonged ventricular relaxation than the control group, there was little difference in the improvement of relaxation with pacing between the two groups.

Thus, Fontan circulation was associated with limited inotropic response and worsening of diastolic filling with increased HR, leading to decreased ESP and elevation of CVP at higher HR.

Responses to beta-adrenergic stimulation.   There was no significant difference in any of the measured parameters between baseline before dobutamine infusion and initial baseline before pacing (Table 2). Therefore, changes relative to baseline immediately before dobutamine infusion are shown in Table 4. In control subjects, dobutamine significantly increased CI and ventricular contractility and significantly improved ventricular relaxation (all p < 0.01 vs. baseline). Notably, the improvement in contractile and diastolic function in the Fontan group was similar to the improvement observed in control group (all p < 0.01 vs. baseline; p = NS vs. control). However, the increase in CI in the Fontan group was significantly smaller than the increase in CI in the control group. To elucidate factors responsible for the limited increase in CI in response to dobutamine in the Fontan group, we performed multivariate analysis of changes in HR, afterload (Ea), preload (EDAI), and contractility (Ees), as well as group effect, as independent variables. We found that only the changes in EDAI significantly correlated with the change in CI, indicating that limited preload reserve was the cause of the decreased response of CI to beta-adrenergic stimulation under Fontan circulation.


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  		Table 4. Changes After Dobutamine Infusion
 

   Discussion
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 Methods
 Results
 Discussion
References
 
Although it seems somewhat intuitive that the absence of a pulmonary ventricle in the Fontan circuit is disadvantageous and may be related to the reported adverse outcomes of this procedure, there have been no detailed analyses of the effects of right heart bypass on ventricular performance and resultant overall hemodynamics. The present study provides novel findings in this regard by separately quantifying ventricular contractile and diastolic function and loading factors, both at rest and under heart-stimulating conditions.

Resting cardiac performance in Fontan circulation.   Under resting conditions, Fontan patients exhibited increased Ea, with Ees comparable to that of control subjects, indicating abnormal ventricular-vascular coupling due to increased afterload. As a result of the increased afterload, but not as a result of the decreased contractility, CI and FS were significantly lower in Fontan patients than in control subjects. The majority of previous studies of systolic function in patients with Fontan circulation relied on measurements with complex interdependence between cardiac properties and loading factors. The results of those studies generally suggest that abnormal systolic function is inherent in Fontan circulation (5,6,18,19), but the results of the present P-A analysis clearly indicate that Fontan physiology is not necessarily associated with decreased ventricular contractility at rest. Although pre-existing volume overload and/or cyanosis may have deleterious effects on contractile elements of a Fontan ventricle, global ventricular contractile function remains preserved in this study of Fontan patients with optimal results who are asymptomatic with good functional status. Thus, depressed contractility is not inherent in Fontan physiology, despite frequent inferences to the contrary in previous reports. The present results suggest that afterload-reducing agents can improve Fontan hemodynamics by improving ventricular-vascular interaction; that possibility should be investigated in clinical trials.

In the present study, ventricular relaxation ({tau} and PFR) was significantly reduced in the Fontan patients. These findings are consistent with those of a series of elegant studies conducted by Penny et al. (20,21). Importantly, although they inferred that this phenomenon may be important for ventricular filling and may be related to decline in functional states of Fontan patients, the present findings clearly indicate that delayed relaxation has minimal effects on net ventricular filling capacity, even at elevated HR (discussed in later text). Thus, Fontan physiology is associated with relaxation abnormality, but the effects of this abnormality on overall hemodynamics appear to be insignificant.

The present findings also represent the first demonstration of chamber-specific diastolic stiffness in the Fontan ventricle, using EDPAR as the index of chamber diastolic stiffness (16,17). Interestingly, we observed no significant difference in chamber stiffness between the Fontan and control groups at baseline. One previous study suggests that increased diastolic stiffness occurs late after Fontan surgery, as indicated by the high prevalence of mid-diastolic flow (22). However, mid-diastolic flow is influenced by several factors other than chamber stiffness (23) and is often observed even in normal subjects (23). Thus, resting diastolic chamber stiffness does not appear to be specifically affected by Fontan circulation.

Responses to increased HR with pacing.   The systolic force generated by the heart increases with increasing HR (24). An increase in HR also enhances diastolic ventricular performance (24,25). The enhancements of systolic force and diastolic performance with increased HR are usually diminished in cases of heart failure (25), and these changes are partly responsible for the limited exercise capacity associated with heart failure (7,26). The present findings represent the first clear demonstration of diminished contractile response and reduced filling capacity with elevated HR in Fontan physiology. Fogel et al. (27) reported a marked decrease in ventricular systolic centroid motion (decreased intensity of contraction) in Fontan patients regardless of ventricular morphology, probably due to restricted ventricular motion resulting from intra-atrial baffle. This mechanism may become evident at high HR and may account for the limited contractile reserve of Fontan patients at elevated HR. The absence of a second ventricular pumping chamber in Fontan circulation may also directly contribute to this reduction of contractile reserve, because the presence of normal left and right ventricles is important for augmentation of the systolic force generated by each ventricle (ventricular-ventricular interaction) (28).

The abnormal ventricular filling with elevated HR in Fontan circulation may be due to increased ventricular chamber viscous behavior or an internal tethering linking atrial contraction force with ventricular diastole (16,29), both of which can be exacerbated by Fontan circulation (27,30). Contractile limitation (limited decrease in ESA) could also interactively affect filling capacity at high HR, because higher ESA can cause a rise in minimum pressure during diastole (16,31). Importantly, relaxation abnormality observed at baseline does not account for reduced ventricular filling at higher HR in Fontan patients, because relaxation similarly improved with increased HR in both the Fontan and control group.

Several studies indicate that peak HR during exercise is significantly lower after Fontan surgery (6,32). Karpawich et al. (33) reported that rate-responsive pacing does not improve exercise performance in Fontan patients with symptomatic bradycardia. However, there is as yet no clear explanation of the mechanism underlying such phenomena. The present data indicating diminished contractile response and reduction of filling capacity with increased HR suggest underlying cardiac mechanisms for the rate-related abnormal phenomena observed in patients with Fontan physiology.

Responses to beta-adrenergic stimulation.   In addition to changes in cardiac function in response to increased HR, beta-adrenergic responsiveness is an important determinant of cardiac performance (8,34). The present Fontan patients had a ventricular contractile response to dobutamine that was comparable to that of the controls. However, the increase in CI induced by dobutamine was significantly smaller for the Fontan group than for the control group, primarily owing to the limited preload reserve associated with Fontan circulation. This sharply contrasts with the diminished beta-adrenergic responsiveness observed in adult cases of heart failure, in which diminished contractile response is a common feature (8,34), and thus further highlights the limitations inherent in Fontan circulation. The lack of pulmonary ventricular energy propelling venous flow into the "single ventricle" in Fontan physiology may be a cause of the reduced preload reserve observed during dobutamine infusion (35). In addition, the loss of augmentation of flow pulsatility in Fontan pulmonary circulation may reduce release of endothelium-derived nitric oxide, thereby attenuating the lowering of pulmonary vascular resistance induced by nitric oxide (36). The diminished beta-adrenergic reserve observed in cases of congestive heart failure is closely related to the decreased exercise capacity seen in heart failure patients (8,34). Thus, the present results may at least partly explain the decreased exercise tolerance observed in patients after the Fontan procedure, although the underlying mechanisms may differ from those implicated in congestive heart failure patients (preload vs. contractility).

Conclusions.   Fontan circulation is associated with increases in ventricular afterload, resulting in decreased CI due to ventricular-vascular mismatch. In addition, Fontan physiology appears to have deleterious effects on cardiac reserve function in response to increased HR or beta-adrenergic stimulation. Because normal ventricular-vascular interaction and augmentation of cardiac performance by these heart-stimulating effects are important for maintenance of cardiac output and exercise capacity, the present results may have important implications for the mechanisms underlying adverse outcome after Fontan surgery. Therefore, to improve the long-term prognosis of patients after Fontan surgery, there is a need for medical interventions that can overcome such limitations inherent in Fontan physiology.


   Footnotes
 
Supported by a national grant (no. 8025127) from the Japan Society for the Promotion of Science and Medical Research Grants from Nipro Corporation, Kawano Memorial Foundation, and Tenshino Medical Institution.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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