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Left Ventricular Function in Adult Patients With Atrial Septal Defect: Implication for Development of Heart Failure After Transcatheter Closure
Journal of Cardiac Failure Vol. 17 No. 11 2011
Left Ventricular Function in Adult Patients With Atrial Septal Defect: Implication for Development of Heart Failure After Transcatheter Closure SATOSHI MASUTANI, MD, FAHA, AND HIDEAKI SENZAKI, MD, FJCC, FACC, FAHA Saitama, Japan
ABSTRACT Despite advances in device closure for atrial septal defect (ASD), post-closure heart failure observed in adult patients remains a clinical problem. Although right heart volume overload is the fundamental pathophysiology in ASD, the post-closure heart failure characterized by acute pulmonary congestion is likely because of age-related left ventricular diastolic dysfunction, which is manifested by acute volume loading with ASD closure. Aging also appears to play important roles in the pathophysiology of heart failure through several mechanisms other than diastolic dysfunction, including ventricular systolic and vascular stiffening and increased incidence of comorbidities that significantly affect cardiovascular function. Recent studies suggested that accurate assessment of preclosure diastolic function, such as test ASD occlusion, may help identify high-risk patients for post-closure heart failure. Antieheart failure therapy before device closure or the use of fenestrated device appears to be effective in preventing post-closure heart failure in the high-risk patients. However, the long-term outcome of such patients remains to be elucidated. Future studies are warranted to construct an algorithm to identify and treat patients at high risk for heart failure after device closure of ASD. (J Cardiac Fail 2011;17:957e963) Key Words: Atrial septal defect, mitral annular velocity, device closure, relaxation, stiffness, aging.
Recent development in device closure for atrial septal defect (ASD),1 which has become a common routine practice, provides a therapeutic option that is associated with fewer complications and faster hemodynamic adaptation,2e5 compared with surgical closure.6,7 However, the development of heart failure, manifested mainly by pulmonary congestion, following device closure of ASD has widely been reported, especially in elderly patients.8e10
Left-to-right intra-atrial shunt through the defect causes not only right heart volume overload, but also left heart volume underload. Abnormalities in left ventricular (LV) diastolic function from long-lasting hemodynamics and age-related changes may also exist particularly in older patients with ASD and be responsible for post-closure heart failure. Given the low risk of complications related to the transcatheter closure of ASD, the development of heart failure after the procedure must be rectified to further refine this treatment modality. For this purpose, it is necessary to understand LV pathophysiology that leads to heart failure after the closure. This review article summarizes current knowledge on LV mechanics both before and after ASD closure, with a particular focus on the potentially relevant factor(s) responsible for the development of post-closure heart failure. We then discuss how such LV pathophysiology needs to be factored into clinical decision-making when considering ASD closure, particularly in terms of identification and treatment of high-risk patients for heart failure development after ASD closure.
From the Department of Pediatric Cardiology, International Medical Center, Saitama Medical University, Saitama, Japan. Manuscript received September 30, 2010; revised manuscript received June 25, 2011; revised manuscript accepted July 6, 2011. Reprint requests: Hideaki Senzaki, MD, FJCC, FACC, FAHA, Staff Office Building 303, Department of Pediatric Cardiology, International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298 Japan. Tel: þ81 42 984 4297; Fax: þ81 42 984 4569. E-mail: [email protected] A national grant (no. 8025127) from the Japan Society for the Promotion of Science and Medical Research (H.S.), grants from Nipro Corporation (H.S.), Kawano Memorial Foundation (H.S.), Saitama Medical University Internal Grant (No. 212208, H.S.), and Tenshindo Medical Institution (Dr. Senzaki). Supported by grants from Nipro Corporation (H.S.), Kawano Memorial Foundation (No. 10-3, H.S.), Saitama Medical University Internal Grant (No. 212208, H.S.), and Tensindo Medical Institution (H.S.). See page 961 for disclosure information. 1071-9164/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2011.07.003
LV Function in ASD Because ASD represents a hemodynamic abnormality of right ventricular (RV) volume overload induced by left-to957
958 Journal of Cardiac Failure Vol. 17 No. 11 November 2011 right shunt at the atrial level, LV function has been studied less extensively than the RV function. Nonetheless, a number of previous studies provided important information about LV mechanics in this disease that could be relevant to the mechanism(s) involved in the development of heart failure after device closure (Table 1). Because the symptoms of heart failure after ASD closure are best characterized by pulmonary congestion, abnormal LV filling should be the key pathophysiological mechanism of heart failure. Indeed, diminished LV filling capacity of ASD is suggested by the fact that LV end-diastolic pressure (EDP) is often comparable to or greater than that of normal subjects despite reduced LVend-diastolic volume because of left-to- right shunt through the ASD.11e13 This was clearly shown in 2 previous studies that employed LV diastolic pressure-volume relationship during one cardiac cycle.11,13 These studies showed a leftward and upward shift of diastolic pressure-volume relationship (Fig. 1).13 Although these results support the notion of diminished LV diastolic capacity in ASD, the diastolic pressure-volume relationship during 1 cardiac cycle is influenced by several factors,14 including the intrinsic (chamber-specific) diastolic stiffness, effects of external constraint, relaxation, and ongoing filling (viscosity/inertia). Therefore, whether diminished LV filling capacity in ASD is important as a pathomechanism of heart failure after ASD closure depends on whether the factors that induce the diminished filling persist after elimination of RV volume load by ASD closure (in other words, whether such factors are intrinsic to LV independent of RV volume load). In this sense, external constraint and viscosity/inertia are reduced or normalized after elimination of RV volume load with ASD closure. Thus, increased passive stiffness and/or impaired relaxation should be important factor(s) in the pathophysiology of heart failure. The end-diastolic pressure-volume relationship during transient loading manipulation15 can be used to assess chamber-specific diastolic stiffness.16 Unfortunately, there has been no such study conducted so far in adults with ASD. However, the study conducted in pediatric population by our group could provide important insight into the pathophysiology of LV diastolic filling in this condition. Our study demonstrated a parallel upward shift of the relationship in ASD pediatric patients, without any change in the slope of the relationship, compared with the control subjects, suggesting the importance of external constraint by the dilated right heart.17 In addition, LV end-diastolic pressure-volume relationship showed parallel downward shift immediately after ASD closure (Fig. 2, unpublished data). Therefore, the diminished filling capacity in ASD could be attributed, at least in part, to right heart volume load rather than increased LV passive stiffness. This is consistent with the clinical observation that despite the suggested LV filling abnormality, the majority of the patients do not develop heart failure after the closure. On the other hand, an increase in chamber-specific LV diastolic stiffness has been suggested in adult patients with ASD. Lim et al18 studied the pressure-volume relationship during transient load manipulation by phenylephrine
infusion both before and immediately after ASD device closure in adults. Although they did not specifically study the end-diastolic pressure-volume relationship, but rather focused on the LV systolic function, the actual pressure-volume loops after ASD closure indicated a marked rise in EDP with an increase in end-diastolic volumes, indicating a steep slope of end-diastolic pressure-volume relationship and hence increased diastolic passive stiffness. Taken together with our results in children indicating no apparent increase in passive stiffness, aging appears to affect LV diastolic chamber stiffness that could lead to the development of heart failure after the closure.19,20 This is consistent with our recent observation of age-dependent increase in LV chamber stiffness in ASD patients, as estimated by tissue Doppler echocardiography.20 Whether the age-associated increase in LV chamber stiffness is amplified by ASD (ie, chronic underloaded condition) and is beyond the levels of adults without cardiovascular disease must await further study. Another factor that can contribute to the diminished LV filling capacity and thus be relevant to post-closure heart failure is abnormal ventricular relaxation. Studies using tissue Doppler echocardiography demonstrated normal to low values of early diastolic mitral annular velocity (e0 ), an index of ventricular relaxation,21e23 in some ASD patients,24 consistent with impaired relaxation. Direct measurement of LV pressure decay25 also indicated normal to prolonged relaxation time constant in both children and adults with ASD.13 Importantly, Satoh et al demonstrated that prolongation of relaxation is observed only in ASD patients with large left-to-right shunt (pulmonary to systemic flow ratio O3),13 again highlighting the importance of ventricular interdependence. On the other hand, aging is also known to impair LV relaxation and thus may cause intrinsic rather than RV volume loadeinduced abnormal LV relaxation that contributes to the heart failure after ASD closure. In this regard, we have demonstrated that age-associated prolongation of LV relaxation is related to a pronounced increase in plasma brain natriuretic peptide after device closure.8 Therefore, the relaxation abnormality reported in ASD patients could be in part because of a dilated right ventricle, but age-associated LV relaxation abnormality could also contribute to the development of post-closure heart failure. The latter possibility will be further discussed later.
LV Function after ASD Device Closure Assessment of LV function after ASD device closure allows the identification of those factors that contribute to the impaired filling capacity in ASD and their importance in the pathophysiology of post-closure heart failure. To date, studies were limited to those factors related to changes in relaxation, but there seem to be some disagreement in their results. Transesophageal echocardiography immediately before and after ASD device closure showed no significant changes in the early diastolic mitral annular velocity (e0 ) and color M-mode velocity of propagation, indexes of relaxation.26
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Table 1. Summary of Reported Hemodynamics and Diastolic Function Before and After ASD Closure
Heart rate and cardiac dimensions/volume Heart rate (beats/min) RV diameter/volume LV diameter/volume LA dimension/volume Diastolic function Left atrial pressure (mm Hg) LV end-diastolic pressure LV tau LVedp/dt max k Mitral E/A e0 septum E/e0 Diastolic P-V relation in one cardiac cycle ED P-V relation during load-manipulation
Baseline
After ASD Closure
[(47) Y(12)
/ Y (29,47,48) [(29,49-51) [(49), /(29), Y(50)
/(12) /with Qp/Qs!3 (13), [with Qp/QsO3 (13) /with Qp/Qs!3 (13), Ywith Qp/Qs!3 (13) /(13) /(28)
[(9,39), /(9) [(18) /(18) /(18) /(29), /without (9) and [with pathological LA pressure rise during test occlusion (9) /(5,27), Y(24,28,29) [(29)
Left and upper shift (13) Parallel downward shift (unpublished)
[, greater than control or increased after ASD closure; /, not significantly different from the control or no significant change after ASD closure; Y, smaller than control or decreased after ASD closure; RV, right ventricle; LV, left ventricle; tau, time constant of ventricular relaxation; Qp/Qs, the ratio of pulmonary to systemic flow; k, stiffness constant; E, peak mitral inflow velocity during early diastole; A, peak mitral inflow velocity during late diastole; e0 , peak mitral annular velocity during early diastole; P-V, pressure-volume; ED, end-diastolic. Numbers in parentheses represent reference numbers in the Reference list.
Similar results were also reported by other groups using tissue Doppler imaging.5,27 These results are consistent with the invasive data indicating no significant change in the time constant of isovolumic relaxation with ASD closure.18 On the other hand, several other studies reported a decrease in e0 just after or within 24 to 48 hours of ASD closure.24,28,29 However, the e0 value returned to the baseline (preclosure) at 6 months or later after the procedure.24 These conflicting results are by themselves supportive of the notion that external constraint by RV volume load, which is reduced with ASD closure, has a significant impact on the delayed relaxation observed in ASD, as discussed previously. On the other hand, volume loading on LV after ASD closure generally
accompanies the rise in systolic pressure, which should slow the relaxation,22,30 and thus counteracts the effects of volume unloading on RV. Therefore, if the preclosure relaxation abnormality is intrinsic to LV and is beyond the level at which the abnormality can be compensated by the improvement induced by RV unloading, then the relaxation abnormality can be amplified with ASD closure. There are only a few studies that have specifically targeted this issue, but our previous data indicated further worsening of the markedly prolonged preclosure relaxation after closure, and that such worsening was associated with the development of heart failure.8 Therefore, delayed relaxation observed in ASD is due in part to RVoverload, but abnormal relaxation, intrinsic to LV property, may also exist and may contribute to the development of pulmonary congestion after the closure. Heart Failure After ASD Closure As discussed previously, although reduced LV filling capacity appears to play a central role in the development of heart failure after device closure of ASD, diastolic function, both before and after ASD closure, is not necessarily uniform, and as such, heart failure after ASD closure does not occur in all patients. Therefore, it is important to identify patients at high risk of postprocedural heart failure before such procedure for a better management of such patients. The following section discusses this clinically important issue based on the currently available data.
Fig. 1. Representative examples of left ventricular pressure-volume relationships during diastole of 1 cardiac cycle in a normal control and atrial septal defect (ASD) patient with pulmonary-to-systemic output ratio O3. Note the upward and leftward displacement of the pressure-volume relationship in the ASD patient. Reprinted with permission from Satoh et al.13
Risk Factors of Post-closure Heart Failure and Their Detection Based on the premise that LV diastolic dysfunction is an etiological factor in post-closure heart failure, it is reasonable to assume that the risk of development of post-closure
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Fig. 2. End-diastolic pressure-volume relationships during inferior vena cava occlusion before (left) and after (right) device closure of atrial septal defect (ASD) in a 9-year-old patient with ASD. The end-diastolic pressure-volume relationship before the closure is reproduced in the right panel (dashed line) to assist comparison. End-diastolic pressure-volume relationship showed parallel downward shift immediately after ASD closure.
heart failure increases with increased severity of the diastolic dysfunction. In this regard, our group demonstrated previously that the baseline e0 value (before ASD closure) is an independent predictor of brain natriuretic peptide levels after ASD closure.8 We also reported that 2 patients with the lowest e0 values presented with symptoms of heart failure (cases A and B in Fig. 3),8 suggesting that noninvasive assessment of relaxation abnormality may help identify patients at high risk for heart failure. Other groups also suggested that a simple measurement of preclosure left atrial pressure may be useful for identification of high-risk patients, because patients with markedly high left atrial pressure after closure, compared with those without (23 vs. 4 mm Hg after closure), had higher baseline left atrial pressure (14 vs. 3 mm Hg before closure) despite similar levels of pulmonary-to-systemic shunt ratio.9 Because the indexes of diastolic function, including e0 and left atrial pressure, are influenced by factors other than diastolic function, most importantly loading status, incorporating the indexes in LV volume status (such as pulmonary-to-systemic shunt ratio) may prove the usefulness of these baseline parameters in risk stratification of patients with ASD for the development of heart failure after the procedure. In addition to diastolic dysfunction, aging could be an important factor in risk stratification for post-closure heart failure. There are several possible mechanisms through which aging can cause post-closure development of heart failure. First, as discussed earlier, aging is associated with ventricular diastolic dysfunction, including ventricular diastolic stiffening (increased diastolic passive stiffness)20 and impairment of relaxation.31e33 Second, aging also causes ventricular systolic and vascular stiffening.34,35 These changes can interact to amplify the increase in blood pressure to a given increase in
preload volume, causing marked delay in relaxation with resultant rise in EDP.36 Third, although most studies reported preserved LV systolic function in ASD, chronic underloaded condition37 superimposed on the aged ventricle may induce LV contractile dysfunction, which can be manifested by acute volume loading with ASD closure, as reported by Lim et al18; a 79-year-old man demonstrated marked reduction in LV contractility after ASD closure. Last, aging is associated with an increase in the incidence of comorbidities, such as atrial fibrillation/flutter, coronary artery disease and pulmonary/systemic hypertension, which could potentially have a significant impact on cardiovascular function. In particular, atrial arrhythmia is known to influence left ventricular hemodynamics even in the absence of structural heart disease38 and thus may additively/synergistically worsen diastolic function in the presence of ASD. Of note, Schubert et al39 reported that pulmonary hypertension (76% vs. 43%; P ! .001) and atrial fibrillation (62% vs. 34%; P ! .01) were more frequent in patients who presented with a marked rise in the left atrial pressure after ASD closure than those who did not. Heart failure with preserved ejection fraction is also more common in elderly population.40 This disease typically presents with acute pulmonary edema, but can be easily masked by the volume unloaded condition, as of ASD. Likewise, regardless of the age of the patient, it is important to check before ASD closure any underlying congenital/ acquired cardiac disease such as hypertrophic cardiomyopathy (41), which may be unmasked/exacerbated by ASD closure. Viaene et al41 reported an important case in this regard: a 27-year-old man presented with acute pulmonary edema after ASD closure because of preexisting hypertrophic cardiomyopathy, which was undiagnosed before the closure procedure. The ASD test occlusion is perhaps the best available direct method to evaluate the risk of post-closure heart failure. Ewert et al9 monitored the left atrial pressure and the mitral valve inflow pattern during complete balloon occlusion of the defect in 18 patients older than 60 years of age. Among them, 7 patients showed marked increase in the left atrial pressure and the E/A ratio of the mitral valve inflow. The mean atrial pressure increased up to 27 mm Hg and the v-wave peak values increased to 55 mm Hg. Two patients among the seven received a transcatheter device closure and developed congestive heart failure.9 Thus, there is no doubt that the ASD test occlusion is useful for risk stratification of post-closure development of heart failure by demonstrating intrinsic diastolic abnormality. At this stage, however, there is no clear cutoff value for a safe closure. Management of High-risk Patients of Post-closure Heart Failure After high-risk patients are identified, how should we manage them? Current management options of the highrisk patients for post-closure heart failure include antie heart failure therapy before ASD closure and the use of fenestrated device. Schubert et al reported the usefulness
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Fig. 3. (A) Relationship between plasma levels of brain natriuretic peptide (BNP) levels measured after device closure and lateral mitral annular early diastolic velocities before closure (y 5 0.0419 x þ 2.31, r 5 0.61, P ! .0001). (B) Patients were divided into 10-year age bins to examine the effects of age on BNP levels. BNP levels measured after atrial septal defect closure correlated with early diastolic mitral annular velocity (e0 ). Two patients with subacute exertional dyspnea had the lowest early diastolic mitral annular velocity values (identified as cases A and B). Reprinted with permission from Masutani et al.8
of antiecongestive conditioning therapy, which consists of dopamine, milrinone, and intravenous furosemide, over 48 to 60 hours before definite ASD closure for patients with LV restriction, which was defined as mean left atrial pressure greater than 10 mm Hg in the occlusion test (Table 1B). Such conditioning therapy markedly reduces the mean left atrial pressure both before and after ASD closure, and helps prevent post-closure heart failure; the mean left atrial pressure of 10 mm Hg before closure and 21 mm Hg after closure before conditioning therapy diminished to 5 and 7 mm Hg, respectively, after conditioning therapy.39 The use of the fenestrated device is another therapeutic option for the high-risk patients, and its usefulness is widely reported.10,39,42e46 Fenestrated ASD occlusion was safely accomplished without complications, and is reported to prevent the development of acute left heart failure in high risk patients.43 However, 1 study indicated that the same treatment failed to rectify LV diastolic dysfunction at least several months after the closure with a fenestrated device.42 To date, there are no standard criteria regarding the use of the fenestrated device with regard to the patient selection and the fenestration size. Also, there are no long-term follow-up data regarding the outcome of patients who were categorized as high risk and underwent ASD device closure with fenestration or conditioning therapy. This issue must be clarified to verify the efficacy of these treatment options for high-risk patients. Summary In a subgroup of aged patients, ASD closure is followed by pulmonary congestion, which is mainly the result of agingrelated LV diastolic dysfunction, comprising increased diastolic stiffness and delayed relaxation. Advanced age per se
also increases the risk of development of heart failure after ASD closure through changes in cardiovascular properties other than diastolic dysfunction, as well as increased incidence of comorbidities that potentially affect cardiovascular function. The extremely low incidence of heart failure in pediatric patients with ASD even after surgical repair by cardiopulmonary bypass provides a strong evidence for the importance of aging in the development of heart failure after ASD closure. Antieheart failure therapies before ASD closure and the use of fenestrated device can potentially prevent the development of heart failure in high-risk patients. Further studies are needed to construct a clear algorithm that can identify and treat high-risk patients through accumulation of data on long-term outcome of patients who receive antie heart failure preconditioning therapies and undergo fenestrated device closure.
Disclosures None.
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24. Lange A, Coleman DM, Palka P, Burstow DJ, Wilkinson JL, Godman MJ. Effect of catheter device closure of atrial septal defect on diastolic mitral annular motion. Am J Cardiol 2003;91:104e8. 25. Senzaki H, Fetics B, Chen CH, Kass DA. Comparison of ventricular pressure relaxation assessments in human heart failure: quantitative influence on load and drug sensitivity analysis. J Am Coll Cardiol 1999;34:1529e36. 26. Gomez CA, Ludomirsky A, Ensing GJ, Rocchini AP. Effect of acute changes in load on left ventricular diastolic function during device closure of atrial septal defects. Am J Cardiol 2005;95:686e8. 27. Pascotto M, Santoro G, Caso P, et al. Global and regional left ventricular function in patients undergoing transcatheter closure of secundum atrial septal defect. Am J Cardiol 2005;96:439e42. 28. Pauliks LB, Chan KC, Chang D, et al. Regional myocardial velocities and isovolumic contraction acceleration before and after device closure of atrial septal defects: a color tissue Doppler study. Am Heart J 2005;150:294e301. 29. Masutani S, Taketazu M, Ishido H, et al. Effects of age on hemodynamic changes after transcatheter closure of atrial septal defect: importance of ventricular diastolic function. Heart Vessels 2011 Mar 18. [Epub ahead of print]. 30. Ishida Y, Meisner JS, Tsujioka K, et al. Left ventricular filling dynamics: influence of left ventricular relaxation and left atrial pressure. Circulation 1986;74:187e96. 31. Hees PS, Fleg JL, Dong SJ, Shapiro EP. MRI and echocardiographic assessment of the diastolic dysfunction of normal aging: altered LV pressure decline or load? Am J Physiol Heart Circ Physiol 2004;286:H782e8. 32. Park HS, Naik SD, Aronow WS, Ahn CW, McClung JA, Belkin RN. Ageand sex-related differences in the tissue Doppler imaging parameters of left ventricular diastolic dysfunction. Echocardiography 2007;24:567e71. 33. Prasad A, Popovic ZB, Arbab-Zadeh A, et al. The effects of aging and physical activity on Doppler measures of diastolic function. Am J Cardiol 2007;99:1629e36. 34. Chen CH, Nakayama M, Nevo E, Fetics BJ, Maughan WL, Kass DA. Coupled systolic-ventricular and vascular stiffening with age: implications for pressure regulation and cardiac reserve in the elderly. J Am Coll Cardiol 1998;32:1221e7. 35. Kass DA. Ventricular arterial stiffening: integrating the pathophysiology. Hypertension 2005;46:185e93. 36. Kass DA, Bronzwaer JG, Paulus WJ. What mechanisms underlie diastolic dysfunction in heart failure? Circ Res 2004;94:1533e42. 37. Romano C, Chinali M, Pasanisi F, et al. Reduced hemodynamic load and cardiac hypotrophy in patients with anorexia nervosa. Am J Clin Nutr 2003;77:308e12. 38. Jais P, Peng JT, Shah DC, et al. Left ventricular diastolic dysfunction in patients with so-called lone atrial fibrillation. J Cardiovasc Electrophysiol 2000;11:623e5. 39. Schubert S, Peters B, Abdul-Khaliq H, Nagdyman N, Lange PE, Ewert P. Left ventricular conditioning in the elderly patient to prevent congestive heart failure after transcatheter closure of atrial septal defect. Catheter Cardiovasc Interv 2005;64:333e7. 40. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251e9. 41. Viaene D, Vermeersch P, Van den Branden F. Pulmonary oedema after percutaneous ASD-closure. Acta Cardiol 2010;65:257e60. 42. Peters B, Ewert P, Schubert S, et al. Self-fabricated fenestrated Amplatzer occluders for transcatheter closure of atrial septal defect in patients with left ventricular restriction: midterm results. Clin Res Cardiol 2006;95:88e92. 43. Bruch L, Winkelmann A, Sonntag S, et al. Fenestrated occluders for treatment of ASD in elderly patients with pulmonary hypertension and/or right heart failure. J Interv Cardiol 2008;21:44e9. 44. Althoff TF, Knebel F, Panda A, et al. Long-term follow-up of a fenestrated Amplatzer atrial septal occluder in pulmonary arterial hypertension. Chest 2008;133:283e5. 45. Macdonald ST, Arcidiacono C, Butera G. Fenestrated Amplatzer atrial septal defect occluder in an elderly patient with restrictive left ventricular physiology. Heart 2010;97:438.
LV Function in ASD 46. Elshershari H, Cao QL, Hijazi ZM. Transcatheter device closure of atrial septal defects in patients older than 60 years of age: immediate and follow-up results. J Invasive Cardiol 2008;20:173e6. 47. Yew G, Wilson NJ. Transcatheter atrial septal defect closure with the Amplatzer septal occluder: five-year follow-up. Catheter Cardiovasc Interv 2005;64:193e6. 48. Swan L, Varma C, Yip J, et al. Transcatheter device closure of atrial septal defects in the elderly: technical considerations and short-term outcomes. Int J Cardiol 2006;107:207e10.
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Left Ventricular Function in Adult Patients With Atrial Septal Defect: Implication for Development of Heart Failure After Transcatheter Closure SATOSHI MASUTANI, MD, FAHA, AND HIDEAKI SENZAKI, MD, FJCC, FACC, FAHA Saitama, Japan
ABSTRACT Despite advances in device closure for atrial septal defect (ASD), post-closure heart failure observed in adult patients remains a clinical problem. Although right heart volume overload is the fundamental pathophysiology in ASD, the post-closure heart failure characterized by acute pulmonary congestion is likely because of age-related left ventricular diastolic dysfunction, which is manifested by acute volume loading with ASD closure. Aging also appears to play important roles in the pathophysiology of heart failure through several mechanisms other than diastolic dysfunction, including ventricular systolic and vascular stiffening and increased incidence of comorbidities that significantly affect cardiovascular function. Recent studies suggested that accurate assessment of preclosure diastolic function, such as test ASD occlusion, may help identify high-risk patients for post-closure heart failure. Antieheart failure therapy before device closure or the use of fenestrated device appears to be effective in preventing post-closure heart failure in the high-risk patients. However, the long-term outcome of such patients remains to be elucidated. Future studies are warranted to construct an algorithm to identify and treat patients at high risk for heart failure after device closure of ASD. (J Cardiac Fail 2011;17:957e963) Key Words: Atrial septal defect, mitral annular velocity, device closure, relaxation, stiffness, aging.
Recent development in device closure for atrial septal defect (ASD),1 which has become a common routine practice, provides a therapeutic option that is associated with fewer complications and faster hemodynamic adaptation,2e5 compared with surgical closure.6,7 However, the development of heart failure, manifested mainly by pulmonary congestion, following device closure of ASD has widely been reported, especially in elderly patients.8e10
Left-to-right intra-atrial shunt through the defect causes not only right heart volume overload, but also left heart volume underload. Abnormalities in left ventricular (LV) diastolic function from long-lasting hemodynamics and age-related changes may also exist particularly in older patients with ASD and be responsible for post-closure heart failure. Given the low risk of complications related to the transcatheter closure of ASD, the development of heart failure after the procedure must be rectified to further refine this treatment modality. For this purpose, it is necessary to understand LV pathophysiology that leads to heart failure after the closure. This review article summarizes current knowledge on LV mechanics both before and after ASD closure, with a particular focus on the potentially relevant factor(s) responsible for the development of post-closure heart failure. We then discuss how such LV pathophysiology needs to be factored into clinical decision-making when considering ASD closure, particularly in terms of identification and treatment of high-risk patients for heart failure development after ASD closure.
From the Department of Pediatric Cardiology, International Medical Center, Saitama Medical University, Saitama, Japan. Manuscript received September 30, 2010; revised manuscript received June 25, 2011; revised manuscript accepted July 6, 2011. Reprint requests: Hideaki Senzaki, MD, FJCC, FACC, FAHA, Staff Office Building 303, Department of Pediatric Cardiology, International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298 Japan. Tel: þ81 42 984 4297; Fax: þ81 42 984 4569. E-mail: [email protected] A national grant (no. 8025127) from the Japan Society for the Promotion of Science and Medical Research (H.S.), grants from Nipro Corporation (H.S.), Kawano Memorial Foundation (H.S.), Saitama Medical University Internal Grant (No. 212208, H.S.), and Tenshindo Medical Institution (Dr. Senzaki). Supported by grants from Nipro Corporation (H.S.), Kawano Memorial Foundation (No. 10-3, H.S.), Saitama Medical University Internal Grant (No. 212208, H.S.), and Tensindo Medical Institution (H.S.). See page 961 for disclosure information. 1071-9164/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2011.07.003
LV Function in ASD Because ASD represents a hemodynamic abnormality of right ventricular (RV) volume overload induced by left-to957
958 Journal of Cardiac Failure Vol. 17 No. 11 November 2011 right shunt at the atrial level, LV function has been studied less extensively than the RV function. Nonetheless, a number of previous studies provided important information about LV mechanics in this disease that could be relevant to the mechanism(s) involved in the development of heart failure after device closure (Table 1). Because the symptoms of heart failure after ASD closure are best characterized by pulmonary congestion, abnormal LV filling should be the key pathophysiological mechanism of heart failure. Indeed, diminished LV filling capacity of ASD is suggested by the fact that LV end-diastolic pressure (EDP) is often comparable to or greater than that of normal subjects despite reduced LVend-diastolic volume because of left-to- right shunt through the ASD.11e13 This was clearly shown in 2 previous studies that employed LV diastolic pressure-volume relationship during one cardiac cycle.11,13 These studies showed a leftward and upward shift of diastolic pressure-volume relationship (Fig. 1).13 Although these results support the notion of diminished LV diastolic capacity in ASD, the diastolic pressure-volume relationship during 1 cardiac cycle is influenced by several factors,14 including the intrinsic (chamber-specific) diastolic stiffness, effects of external constraint, relaxation, and ongoing filling (viscosity/inertia). Therefore, whether diminished LV filling capacity in ASD is important as a pathomechanism of heart failure after ASD closure depends on whether the factors that induce the diminished filling persist after elimination of RV volume load by ASD closure (in other words, whether such factors are intrinsic to LV independent of RV volume load). In this sense, external constraint and viscosity/inertia are reduced or normalized after elimination of RV volume load with ASD closure. Thus, increased passive stiffness and/or impaired relaxation should be important factor(s) in the pathophysiology of heart failure. The end-diastolic pressure-volume relationship during transient loading manipulation15 can be used to assess chamber-specific diastolic stiffness.16 Unfortunately, there has been no such study conducted so far in adults with ASD. However, the study conducted in pediatric population by our group could provide important insight into the pathophysiology of LV diastolic filling in this condition. Our study demonstrated a parallel upward shift of the relationship in ASD pediatric patients, without any change in the slope of the relationship, compared with the control subjects, suggesting the importance of external constraint by the dilated right heart.17 In addition, LV end-diastolic pressure-volume relationship showed parallel downward shift immediately after ASD closure (Fig. 2, unpublished data). Therefore, the diminished filling capacity in ASD could be attributed, at least in part, to right heart volume load rather than increased LV passive stiffness. This is consistent with the clinical observation that despite the suggested LV filling abnormality, the majority of the patients do not develop heart failure after the closure. On the other hand, an increase in chamber-specific LV diastolic stiffness has been suggested in adult patients with ASD. Lim et al18 studied the pressure-volume relationship during transient load manipulation by phenylephrine
infusion both before and immediately after ASD device closure in adults. Although they did not specifically study the end-diastolic pressure-volume relationship, but rather focused on the LV systolic function, the actual pressure-volume loops after ASD closure indicated a marked rise in EDP with an increase in end-diastolic volumes, indicating a steep slope of end-diastolic pressure-volume relationship and hence increased diastolic passive stiffness. Taken together with our results in children indicating no apparent increase in passive stiffness, aging appears to affect LV diastolic chamber stiffness that could lead to the development of heart failure after the closure.19,20 This is consistent with our recent observation of age-dependent increase in LV chamber stiffness in ASD patients, as estimated by tissue Doppler echocardiography.20 Whether the age-associated increase in LV chamber stiffness is amplified by ASD (ie, chronic underloaded condition) and is beyond the levels of adults without cardiovascular disease must await further study. Another factor that can contribute to the diminished LV filling capacity and thus be relevant to post-closure heart failure is abnormal ventricular relaxation. Studies using tissue Doppler echocardiography demonstrated normal to low values of early diastolic mitral annular velocity (e0 ), an index of ventricular relaxation,21e23 in some ASD patients,24 consistent with impaired relaxation. Direct measurement of LV pressure decay25 also indicated normal to prolonged relaxation time constant in both children and adults with ASD.13 Importantly, Satoh et al demonstrated that prolongation of relaxation is observed only in ASD patients with large left-to-right shunt (pulmonary to systemic flow ratio O3),13 again highlighting the importance of ventricular interdependence. On the other hand, aging is also known to impair LV relaxation and thus may cause intrinsic rather than RV volume loadeinduced abnormal LV relaxation that contributes to the heart failure after ASD closure. In this regard, we have demonstrated that age-associated prolongation of LV relaxation is related to a pronounced increase in plasma brain natriuretic peptide after device closure.8 Therefore, the relaxation abnormality reported in ASD patients could be in part because of a dilated right ventricle, but age-associated LV relaxation abnormality could also contribute to the development of post-closure heart failure. The latter possibility will be further discussed later.
LV Function after ASD Device Closure Assessment of LV function after ASD device closure allows the identification of those factors that contribute to the impaired filling capacity in ASD and their importance in the pathophysiology of post-closure heart failure. To date, studies were limited to those factors related to changes in relaxation, but there seem to be some disagreement in their results. Transesophageal echocardiography immediately before and after ASD device closure showed no significant changes in the early diastolic mitral annular velocity (e0 ) and color M-mode velocity of propagation, indexes of relaxation.26
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Table 1. Summary of Reported Hemodynamics and Diastolic Function Before and After ASD Closure
Heart rate and cardiac dimensions/volume Heart rate (beats/min) RV diameter/volume LV diameter/volume LA dimension/volume Diastolic function Left atrial pressure (mm Hg) LV end-diastolic pressure LV tau LVedp/dt max k Mitral E/A e0 septum E/e0 Diastolic P-V relation in one cardiac cycle ED P-V relation during load-manipulation
Baseline
After ASD Closure
[(47) Y(12)
/ Y (29,47,48) [(29,49-51) [(49), /(29), Y(50)
/(12) /with Qp/Qs!3 (13), [with Qp/QsO3 (13) /with Qp/Qs!3 (13), Ywith Qp/Qs!3 (13) /(13) /(28)
[(9,39), /(9) [(18) /(18) /(18) /(29), /without (9) and [with pathological LA pressure rise during test occlusion (9) /(5,27), Y(24,28,29) [(29)
Left and upper shift (13) Parallel downward shift (unpublished)
[, greater than control or increased after ASD closure; /, not significantly different from the control or no significant change after ASD closure; Y, smaller than control or decreased after ASD closure; RV, right ventricle; LV, left ventricle; tau, time constant of ventricular relaxation; Qp/Qs, the ratio of pulmonary to systemic flow; k, stiffness constant; E, peak mitral inflow velocity during early diastole; A, peak mitral inflow velocity during late diastole; e0 , peak mitral annular velocity during early diastole; P-V, pressure-volume; ED, end-diastolic. Numbers in parentheses represent reference numbers in the Reference list.
Similar results were also reported by other groups using tissue Doppler imaging.5,27 These results are consistent with the invasive data indicating no significant change in the time constant of isovolumic relaxation with ASD closure.18 On the other hand, several other studies reported a decrease in e0 just after or within 24 to 48 hours of ASD closure.24,28,29 However, the e0 value returned to the baseline (preclosure) at 6 months or later after the procedure.24 These conflicting results are by themselves supportive of the notion that external constraint by RV volume load, which is reduced with ASD closure, has a significant impact on the delayed relaxation observed in ASD, as discussed previously. On the other hand, volume loading on LV after ASD closure generally
accompanies the rise in systolic pressure, which should slow the relaxation,22,30 and thus counteracts the effects of volume unloading on RV. Therefore, if the preclosure relaxation abnormality is intrinsic to LV and is beyond the level at which the abnormality can be compensated by the improvement induced by RV unloading, then the relaxation abnormality can be amplified with ASD closure. There are only a few studies that have specifically targeted this issue, but our previous data indicated further worsening of the markedly prolonged preclosure relaxation after closure, and that such worsening was associated with the development of heart failure.8 Therefore, delayed relaxation observed in ASD is due in part to RVoverload, but abnormal relaxation, intrinsic to LV property, may also exist and may contribute to the development of pulmonary congestion after the closure. Heart Failure After ASD Closure As discussed previously, although reduced LV filling capacity appears to play a central role in the development of heart failure after device closure of ASD, diastolic function, both before and after ASD closure, is not necessarily uniform, and as such, heart failure after ASD closure does not occur in all patients. Therefore, it is important to identify patients at high risk of postprocedural heart failure before such procedure for a better management of such patients. The following section discusses this clinically important issue based on the currently available data.
Fig. 1. Representative examples of left ventricular pressure-volume relationships during diastole of 1 cardiac cycle in a normal control and atrial septal defect (ASD) patient with pulmonary-to-systemic output ratio O3. Note the upward and leftward displacement of the pressure-volume relationship in the ASD patient. Reprinted with permission from Satoh et al.13
Risk Factors of Post-closure Heart Failure and Their Detection Based on the premise that LV diastolic dysfunction is an etiological factor in post-closure heart failure, it is reasonable to assume that the risk of development of post-closure
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Fig. 2. End-diastolic pressure-volume relationships during inferior vena cava occlusion before (left) and after (right) device closure of atrial septal defect (ASD) in a 9-year-old patient with ASD. The end-diastolic pressure-volume relationship before the closure is reproduced in the right panel (dashed line) to assist comparison. End-diastolic pressure-volume relationship showed parallel downward shift immediately after ASD closure.
heart failure increases with increased severity of the diastolic dysfunction. In this regard, our group demonstrated previously that the baseline e0 value (before ASD closure) is an independent predictor of brain natriuretic peptide levels after ASD closure.8 We also reported that 2 patients with the lowest e0 values presented with symptoms of heart failure (cases A and B in Fig. 3),8 suggesting that noninvasive assessment of relaxation abnormality may help identify patients at high risk for heart failure. Other groups also suggested that a simple measurement of preclosure left atrial pressure may be useful for identification of high-risk patients, because patients with markedly high left atrial pressure after closure, compared with those without (23 vs. 4 mm Hg after closure), had higher baseline left atrial pressure (14 vs. 3 mm Hg before closure) despite similar levels of pulmonary-to-systemic shunt ratio.9 Because the indexes of diastolic function, including e0 and left atrial pressure, are influenced by factors other than diastolic function, most importantly loading status, incorporating the indexes in LV volume status (such as pulmonary-to-systemic shunt ratio) may prove the usefulness of these baseline parameters in risk stratification of patients with ASD for the development of heart failure after the procedure. In addition to diastolic dysfunction, aging could be an important factor in risk stratification for post-closure heart failure. There are several possible mechanisms through which aging can cause post-closure development of heart failure. First, as discussed earlier, aging is associated with ventricular diastolic dysfunction, including ventricular diastolic stiffening (increased diastolic passive stiffness)20 and impairment of relaxation.31e33 Second, aging also causes ventricular systolic and vascular stiffening.34,35 These changes can interact to amplify the increase in blood pressure to a given increase in
preload volume, causing marked delay in relaxation with resultant rise in EDP.36 Third, although most studies reported preserved LV systolic function in ASD, chronic underloaded condition37 superimposed on the aged ventricle may induce LV contractile dysfunction, which can be manifested by acute volume loading with ASD closure, as reported by Lim et al18; a 79-year-old man demonstrated marked reduction in LV contractility after ASD closure. Last, aging is associated with an increase in the incidence of comorbidities, such as atrial fibrillation/flutter, coronary artery disease and pulmonary/systemic hypertension, which could potentially have a significant impact on cardiovascular function. In particular, atrial arrhythmia is known to influence left ventricular hemodynamics even in the absence of structural heart disease38 and thus may additively/synergistically worsen diastolic function in the presence of ASD. Of note, Schubert et al39 reported that pulmonary hypertension (76% vs. 43%; P ! .001) and atrial fibrillation (62% vs. 34%; P ! .01) were more frequent in patients who presented with a marked rise in the left atrial pressure after ASD closure than those who did not. Heart failure with preserved ejection fraction is also more common in elderly population.40 This disease typically presents with acute pulmonary edema, but can be easily masked by the volume unloaded condition, as of ASD. Likewise, regardless of the age of the patient, it is important to check before ASD closure any underlying congenital/ acquired cardiac disease such as hypertrophic cardiomyopathy (41), which may be unmasked/exacerbated by ASD closure. Viaene et al41 reported an important case in this regard: a 27-year-old man presented with acute pulmonary edema after ASD closure because of preexisting hypertrophic cardiomyopathy, which was undiagnosed before the closure procedure. The ASD test occlusion is perhaps the best available direct method to evaluate the risk of post-closure heart failure. Ewert et al9 monitored the left atrial pressure and the mitral valve inflow pattern during complete balloon occlusion of the defect in 18 patients older than 60 years of age. Among them, 7 patients showed marked increase in the left atrial pressure and the E/A ratio of the mitral valve inflow. The mean atrial pressure increased up to 27 mm Hg and the v-wave peak values increased to 55 mm Hg. Two patients among the seven received a transcatheter device closure and developed congestive heart failure.9 Thus, there is no doubt that the ASD test occlusion is useful for risk stratification of post-closure development of heart failure by demonstrating intrinsic diastolic abnormality. At this stage, however, there is no clear cutoff value for a safe closure. Management of High-risk Patients of Post-closure Heart Failure After high-risk patients are identified, how should we manage them? Current management options of the highrisk patients for post-closure heart failure include antie heart failure therapy before ASD closure and the use of fenestrated device. Schubert et al reported the usefulness
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Fig. 3. (A) Relationship between plasma levels of brain natriuretic peptide (BNP) levels measured after device closure and lateral mitral annular early diastolic velocities before closure (y 5 0.0419 x þ 2.31, r 5 0.61, P ! .0001). (B) Patients were divided into 10-year age bins to examine the effects of age on BNP levels. BNP levels measured after atrial septal defect closure correlated with early diastolic mitral annular velocity (e0 ). Two patients with subacute exertional dyspnea had the lowest early diastolic mitral annular velocity values (identified as cases A and B). Reprinted with permission from Masutani et al.8
of antiecongestive conditioning therapy, which consists of dopamine, milrinone, and intravenous furosemide, over 48 to 60 hours before definite ASD closure for patients with LV restriction, which was defined as mean left atrial pressure greater than 10 mm Hg in the occlusion test (Table 1B). Such conditioning therapy markedly reduces the mean left atrial pressure both before and after ASD closure, and helps prevent post-closure heart failure; the mean left atrial pressure of 10 mm Hg before closure and 21 mm Hg after closure before conditioning therapy diminished to 5 and 7 mm Hg, respectively, after conditioning therapy.39 The use of the fenestrated device is another therapeutic option for the high-risk patients, and its usefulness is widely reported.10,39,42e46 Fenestrated ASD occlusion was safely accomplished without complications, and is reported to prevent the development of acute left heart failure in high risk patients.43 However, 1 study indicated that the same treatment failed to rectify LV diastolic dysfunction at least several months after the closure with a fenestrated device.42 To date, there are no standard criteria regarding the use of the fenestrated device with regard to the patient selection and the fenestration size. Also, there are no long-term follow-up data regarding the outcome of patients who were categorized as high risk and underwent ASD device closure with fenestration or conditioning therapy. This issue must be clarified to verify the efficacy of these treatment options for high-risk patients. Summary In a subgroup of aged patients, ASD closure is followed by pulmonary congestion, which is mainly the result of agingrelated LV diastolic dysfunction, comprising increased diastolic stiffness and delayed relaxation. Advanced age per se
also increases the risk of development of heart failure after ASD closure through changes in cardiovascular properties other than diastolic dysfunction, as well as increased incidence of comorbidities that potentially affect cardiovascular function. The extremely low incidence of heart failure in pediatric patients with ASD even after surgical repair by cardiopulmonary bypass provides a strong evidence for the importance of aging in the development of heart failure after ASD closure. Antieheart failure therapies before ASD closure and the use of fenestrated device can potentially prevent the development of heart failure in high-risk patients. Further studies are needed to construct a clear algorithm that can identify and treat high-risk patients through accumulation of data on long-term outcome of patients who receive antie heart failure preconditioning therapies and undergo fenestrated device closure.
Disclosures None.
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