Spontaneous Clinical and Hemodynamic Improvement in Patients on Waiting List for Heart Transplantation

Spontaneous Clinical and Hemodynamic Improvement in Patients on Waiting List for Heart Transplantation* Manuel Anguita, M.D.; Jose M. ArizOn, M.D.; Gregorio Bueno, M.D.; Manuel Concha, M.D.; and Federico Valles, M.D.

Heart transplantation is currently the most effective therapy for patients with severe heart failure due to dilated cardiomyopathy, although long-term survival without transplantation has been described in a few patients. We have identified Bve patients with severe heart failure who experienced a significant clinical and hemodynamic improvement while they were waiting for heart transplantation. At initial assessment, all 6ve patients were symptom-class 4; left ventricular end-diastolic pressure was 33 ± 4 mm Hg, left ventricular ejection fraction was 0.20±0.01, left ventricular end-systolic volume was 130 ± 3 mllminlml , and cardiac index was 2.1 ± 0.1 IJmin/m l • These patients showed a marked improvement at two to ten months after initial assessment, while they were waiting for a donor heart. After a follow-up of 10 to 31 months (mean followup, 20 months), the 6ve patients were still alive and their clinical and hemodynamic condition remained stable. On the contrary, survival was less than 15 percent at six months for the remaining patients with indications for heart trans-

plantation but in whom transplant could not be performed because of the existence of contrainmcatioDS or lack of donors; all these patients were dead at 18 months after initial assessment. The Bve patients who developed spontaneous favorable outcome showed a trend to have higher serum sodium values, shorter symptomatic history, lesser need for intravenous inotropic support, and better response to medical therapy than the other patients. Our 6ndings suggest that some patients with transplants could have experienced a sustained and spontaneous clinical and hemodynamic recovery with medical therapy alone, although it seems currently difficult to identify patients with this favorable outcome. (Che., 1992; 102:96-99)

left ventricular failure is the main cause of Severe death in patients with ischemic or nonischemic

occur in patients with idiopathic or ischemic DCM. We have identified five patients with severe heart failure who developed an unexpected clinical and hemodynamic improvement while they were waiting fora UT.

dilated cardiomyopathy (OCM). Survival for symptomatic patients with DCM is poor. Mortality was 77 percent in 104 patients with symptomatic idiopathic OCM studied at the Mayo Clinic, Rochester, Minn, between 1960 and 1973;1 two thirds of these deaths occurred within the first two years of follow-up. 1 Other authors have reported survival rates of 51 percent at 12 months and 19 percent at 25 months for patients with either ischemic or nonischemic DCM. 2 Prognosis seems worse for patients with severe heart failure, usually in New York Heart Association (NYUA)clinical class 4, referred for heart transplantation (UT). Sixmonth mortality during the early period of HT at Stanford University was over 90 percent for patients receiving medical therapy" Nevertheless, several reports have shown spontaneous improvement and prolonged survival in occasional patients with severe, symptomatic OCM.4 Although this favorable outcome seems more frequent in patients with shorter symptomatic history, acute myocarditis," alcoholic cardiomyopathy,6 or peripartum cardiomyopathy, 7 it may also *From the Heart Transplantation Unit, Hospital Reina Sofia, Universidad de Cordoba, C6rdoba, Spain. Manuscript received October 15; revision accepted January 17. Reprint requests: Dr. Anguita, Seroicio Cardiologia, Hospital Reina Sofia, Avda Menendez Pidal SIN, Cordoba, Spain 14004

98

CI = cardiac index; en = cardiothoracic index; DCM = dilated cardiomyopathy; EMB eodomyocardial biopsy; HT heart transplantation; LVEDP = left ventricular end-diastolic pressure; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; NYHA New York Heart Association; PVR pulmonary vascular resis~

=

=

=

=

MATERIAL AND METHODS

One hundred ten patients with severe NYHA class 4 congestive heart failure were referred for heart transplantation evaluation to our hospital from May 1986 to December 1990. Etiology was idiopathic DCM in 50 percent of patients, ischemic DCM in 36 percent, and valvular heart disease in 14 percent. All patients received intensive medical therapy with digoxin, diuretics, and vasodilators (nitrates and captopril), and nonglycoside inotropic drugs (dopamine, dobutamine, amrinone) when needed. Response to medical therapy was considered positive when a NYHA symptom class 2 could be achieved. All patients underwent an exhaustive clinical, analytical, and hemodynamic evaluation, including right and left heart catheterization and coronary arteriography once the patient was clinically stabilized on a regimen of medical therapy. Endomyocardial biopsy (EMB) was performed in patients with idiopathic DCM; since the risk of the procedure was considered too high in ten patients, EMB was performed in 41 percent of aU patients. Histologic signs of myocarditis were absent in all biopsy specimens. Forty-three patients (39 percent) were considered "too well" for transplantation after clinical and hemodynamic assessment 8114 they were discharged from the hospital on a regimen of oral medical therapy Heart transplantation was considered to be indicated in the other 67 patients, although the existence of medical or nonmedical contraindications precluded it in 20. The reasons for

SpontaneousImprovement in Patients on WaitingList for Heart Transplantation (Anguita et aI)

Table l-Contraindicationa for Cardiac Tranaplantation in Our PatientB No. (%)

Contraindication Pulmonary hypertension" Hepatopathylliver failure Age over 60 yr Psychiatric disturbance Alcoholism Pulmonary disease Malignancy Patient refusal Total

6 (30)

5 (25)

3 2 1 1

(15) (10) (5) (5) 1 (5) 1 (5) 20

*Pulmonary vascular resistance >6 Wood units and/or transpulmonary gradient> 15 mm Hg after vasodilator tests. excluding these 20 patients from the heart transplant program are shown in Table 1. Thirty-seven of the remaining 47 patients underwent transplantation during the period of study Patients on the waiting list for HT were followed up closely; in five, significant clinical improvement and decrease in heart size (on chest roentgenogram or echocardiograpby) were observed, and a second hemodynamic study was performed. Initial and postimprovement clinical and hemodynamic features of these patients will be presented, although statistical differences between the conditions (initial and postimprovement data) have not been tested, due to the small number of cases. In an attempt to identify clinical or hemodynamic parameters that could have been predictors of this favorable outcome, we have compared the features of these five patients with those of the other 62 patients in whom HT also was indicated after initial assessment, including the 20 patients with contraindications for transplant. The Xl test and the non paired Students t test were used for statistical analysis. RESULTS

Main clinical, analytical, and hemodynamic features of our five patients are shown in Table 2. All of them were male, and ages ranged from 34 to 54 years. A history of long-term moderate alcohol intake, 60 to 65 Wda~ was present in two patients (those with shorter symptomatic history, three months). An episode of acute myocarditis was suspected to have occurred seven months before in a third patient on the basis of clinical history, but EMB specimen did not show signs of myocarditis. In the remaining two patients, a long history of severe heart failure (20 to 36 months) was present, and no etiologic factors could be found. Coronary angiography was normal in the five patients. All were NYHA symptom class 4, and right heart failure was a main feature in only one patient. Sustained, more than 30 s, ventricular tachycardia was demonstrated in the patient with suspected acute myocarditis, and another two patients had complex ventricular premature beats on 24-h ambulatory monitoring; all them received treatment with amiodarone. Captopril was administered to all patients; the starting dosage was 6.25 mwS h and then it was titrated to the maximum dosage that did not cause signi6cant hypotension or renal failure. Two of the 6ve patients tolerated high dosages of captopril, 150 mg/day (Table

2). Serum sodium and creatinine clearance were almost normal in all patients (Table 2). Cardiothoracic index (CTI) was over 0.60 in the five patients (Table 2). No significant fibrosis was found in the EMB specimens, and three patients had signs of moderate myocyte hypertrophy. Baseline hemodynamic features are shown in Table 2. Left ventricular end-diastolic pressure (LVEDP) and left ventricular end-systolic volume (LVESV) were elevated and cardiac index (CI) and left ventricular ejection fraction (LVEF) were severely depressed in all five patients. Response to medical therapy was positive in the five patients, and they could be discharged from the hospital on a regimen of oral treatment, remaining on a waiting list for HT with regular priority. One patient had positive cytotoxic antibodies and no suitable donor heart could be found for him. Another two patients were also waiting for transplant seven and ten months, respectively, due to the shortage of donors; one of them refused transplantation after six months of waiting for transplant, because he felt better. In the remaining two patients, a reduction in heart size was observed on a chest roentgenogram at two and five months after initial hospital discharge. Changes from initial values are shown in Table 3. Table 2-Clinical, Analytical, and IIemodynamic FetJtura of Our Five Ibtienta at Initial ~ Features Age, yr Sex, male, % Etiology of DCM: idiopathic, % Symptoms history, mo NYHA symptom class: 4, % Ventricular tachycardia, % Intravenous inotropic support, % Captopril dosage, mg/day Antiarrhythmic drugs, % Positive response to therapy, % LVEF, % PVR, Wood units X m2 LVED~mmHg

Cardiac index, Umin/m1 LVES~ ml/m" Cardiothoracic index, % Serum sodium, mEIL Creatinine clearance, mllmin Fibrosis in EMB, % No Mild Hypertrophy in EMB, %

Results 39 ± 8

100

(34-54)

loot

14 ± 14

100

(3-36)

20 20 85 ± 59 (37-150)

60i 100

20 ± 1 2.4 ± 0.5 33 ± 4 2.1 ±0.1 130±3 65 ± 5 136.6± 1.8 75± 19

(13-22) (1.8-3.3) (25-40) (1.8-2.7) (127-135) (60-70) (134-139) (65-109)

80 20 60

*DCM = dilated cardiomyopathy; NYHA = New York Heart Association; LVEF = left ventricular ejection fraction; PVR = pulmonary vascular resistance; LVEDP = left ventricular enddiastolic pressure; LVESV =left ventricular end-systolic volume; EMB = endomyocardial biopsy. tSuspected acute myocarditis (one patient) and chronic moderate alcohol intake (two patients). iAmiodarone in all cases. CHEST I 102 I 1 I JUL'( 1992

97

Table 3-CliraicGl and Hemodgnamic Chang. in Our Five ftJtienta·

en LVEF LVEDP LVESV CI

Initial

Improvement

65±5 (60-70) 20± 1 (13-22) 33±4 (25-40) 130±3 (127-135) 2.1 ±0.1 (1.8-2.7)

47±2 (45-50) 43±6 (34-51) 19±5 (11-24) Q9± 11 (85-116) 3.3±0.5 (2.9-4.2)

% Change

-28

+ 115 -42

-24 +57

*en = cardiothoracic index (%); LVEF = left ventricular ejection fraction (%); LVEDP = left ventricular end-diastolic pressure (mm Hg), LVESV = left ventricular end-systolic volume (mVml ) ; CI = cardiac index (Umin/ml ) .

Cardiothoracic index decreased to 0.50 or less in all patients. Cardiac index rose over 2.5 Izmin/m", Aland LVESV remained slightly though LVEF, LVEO~ altered, a significant improvement was observed in all patients (Table 3). All patients performed normal physical activity and all but one was NYHA class 1. Results of the comparison between baseline clinical and hemodynamic features of the five patients whose conditions improved spontaneously and those of the other 62 patients in whom HT was indicated (including the 20 patients with contraindications, Table 1) are shown in 'Iable 4. Although no statistically significant differences were found, probably due to the small number of improved patients, these five patients showed a trend to have higher serum sodium levels, shorter symptomatic history, lesser need for intravenous inotropic support, better response to medical therapy and to tolerate higher captopril dosages than patients whose conditions did not improve (p values near 0.1, Table 4). On the contrary, hemodynamic LVES~ and CI) were parameters (LVEF, LVEO~ similar in both groups. Although due to the lack of Table 4-ComptJriaon between Grou,.·

Age, yr Symptom history, mo ~tiology: idiopathic DCM Serum sodium, mEIL Captopril dosage, mwday Intravenous inotropics Antiarrhythmic drugs Positive responset LVEF, % LVED~mmHg

CI, Uminlml LVES~ mVml

Group A (N=5)

GroupB (N=62)

39±2 13±14

45±13 29±27 48% 134±6 36±22

l00'f,

136±2 85±59 20% 60% l00'f,

6O'f,

2O±1 33±5 2.1±0.1 130±3

2O±5 29±8 2.2±0.6 128±40

60%

54%

p Value NS 0.19 0.14 0.06 0.13 0.19 NS 0.14 NS NS NS NS

*Group A includes the 6ve improved patients. Group B includes the other 62 patients in whom heart transplantation was also considered indicated (including patients with contraindications). P values near 0.1 are shown. DCM =dilated cardiomyopathy; LVEF =left ventricular ejection fraction; LVEDP =left ventricular end-diastolic pressure; CI = cardiac index; LVESV = left ventricular end-systolic volume. t Positive response to medical therapy. 88

quantification it could not be statistically compared, myocardial fibrosis seemed to be more extended in patients whose conditions did not improve than in the five patients whose condition did. Probability of survival was less than 15 percent at six months for patients whose conditions did not improve and in whom HT could not be performed because of contraindications or death while waiting for a donor, and mortality was 100 percent at 18 months for this group of patients. Current status of the five patients with improvement after a mean followup of 20.6 months (range, 10 to 31 months) is similar to that mentioned previously (Table 3, "improvement" values). DISCUSSION

Mortality is very high for patients with severe congestive heart failure secondary to ischemic or idiopathic DCM .1-3 Although the development of new vasodilator agents, such as angiotensin-converting enzyme inhibitors, has been demonstrated to decrease short-term mortality in patients with severe heart failure," HT is currently the most effective therapy for these patients," Survival was only 25 percent in patients excluded from HT for nonmedical contraindications in one study; 10 and one-year mortality without transplant was 54 percent in patients considered "too well" for transplantation but in whom LVEF was severely depressed. II In our study, survival was only 30 percent in the patients with initial indication of transplant but in whom it could not be performed because of the existence of contraindications or the shortage of donors (including in this analysis the five patients whose conditions improved spontaneously). Nevertheless, long-term survival has been reported in some patients with severe heart failure due to DCM.l.4 This favorable outcome is more probable in patients with alcoholic or peripartum oeM and acute viral myocarditis. Reversibility of alcoholic OCM has been well documented; two factors may be associated with a favorable course: short duration of symptoms and abstention from alcohol,6.12 but a significant percentage of patients who abstained did not recover. Prognosis in peripartum cardiomyopathy is strongly related to the evolution of heart size 7 : when heart size returns to normal within six months, prognosis is excellent, but 85 percent of women with persistent cardiomegaly died during a follow-up period averaging five years," Acute myocarditis can cause acute DCM; spontaneous improvement occurs in almost 40 percent of patients," but in the remaining patients, death or severe chronic heart failure ensues. One of our five patients could have had an acute myocarditis seven months before referral, and another two had a history of moderate alcohol intake and short symptomatic history. Nevertheless, HT was indicated

Spontaneous Improvement in Patients on WaitIngList for HeartTransplantation (Angulta sf aJ)

based on their impaired hemodynamic condition (Table 2). Low CI and high LVEOP are well-known predictors of poor prognosis.' The other two patients are typical examples of patients with chronic idiopathic OeM and severe heart failure in whom spontaneous recovery is not expected. It seems currently difficult, and even impossible, to predict this favorable outcome in individual patients. LVEF, LVEO~ and CI did not show any difference between patients with favorable or unfavorable outcome (Table 4). Although the differences were not statistically significant, perhaps due to the small number of cases, the five patients whose conditions improved spontaneously showed a trend toward higher serum sodium levels, shorter symptomatic history, and better response to aggressive medical therapy The prognostic role of serum sodium in congestive heart failure is well known." The value of intensive medical therapy has been recently pointed out by Stevenson et al. l " In this study, 50 patients transferred from other hospitals for urgent HT underwent intensive afterload reduction therapy tailored to hemodynamic goals. Forty patients (SO percent) could be discharged from the hospital without surgery, and actuarial survival for 24 discharged patients receiving sustained medical therapy alone was 67 percent at one year. Perhaps pretreatment hemodynamic parameters could have a lesser prognostic value, and the hemodynamic study should be repeated after clinical stabilization with aggressive medical therapy Nevertheless, baseline hemodynamic features of our patients, shown in Tables 2 and 3, were obtained once the conditions of the patients were stabilized. Absence of fibrosis in EMB specimens also was a common feature in our five patients. The percentage of fibrosis on EMB specimens appears to have a prognostic value for some authors. IS Limitations of our study are two. First, the small number of cases does not allow us to obtain statistically significant conclusions. Second, it seems possible that some of the patients who had transplants could also have recovered spontaneously, since their inclusion in the group of patients with theoretical poor outcome would be incorrect. Moreover, left ventricular function continued moderately impaired in all five patients (Table 3), and long-term outcome is not known, since a close follow-up seems necessary. Shortage of donor hearts is currently the main limitation to heart transplant," and its indications and patient priority should be established accurately Our report suggests that some patients who underwent transplantation could have developed a sustained clinical and hemodynamic improvement with medical therapy alone. Although it seems difficult to identify

these patients, some features may be of value. Patients with short symptomatic history, normal serum sodium levels, positive response to medical therapy, long-term alcohol intake, and possible myocarditis should undergo a close clinical and hemodynamic follow-up before the indication for HT is established. REFERENCES

1 Fuster J, Gersh B, Giuliani E, Tajik A, Brandenburg R, Frye R. The natural history of idiopathic dilated cardiomyopathy. Am J Cardioll981; 47:525-31 2 Holmes J, Kubo S, Cody R, Kligfield E Arrhythmias in ischemic and nonischemic dilated cardiomyopathy: prediction of mortality by ambulatory electrocardiography. Am J Cardioll985; 55:14651 3 Jamieson S~ Oyer PE, Reitz RA, Baumgartner WA, Bieber C~ Stinson EB, et al. Cardiac transplantation at Stanford. Heart Transplantation 1982; 1:86-91 4 Goldhaber SZ, Lilly LS, Selwyn A~ Nash DT, Collins JJ. Spontaneous remission and prolonged survival in postinfarction cardiomyopathy Am Heart J 1986; 112:409-12 5 Dec G~ Palacios IF, Fallon JT, Aretz HT, Mills J, Lee DCS, et al, Active myocarditis in the spectrum of acute dilated cardiomyopathies: clinical features, histological correlates and clinical outcome. N Engl J Med 1985; 312:885-90 6 Schwartz L, Sample KA, Wigle ED. Severe alcoholic cardiomyopathy reversed with abstention from alcohol. Am J Cardiol 1975; 36:963-66 7 Demakis JG, Rahimtoola SH, Sutton Ge, Meadows WR, Szanto PB, Tobin JR, et al, Natural course of peripartum cardiomyopathy. Circulation 1971; 44:1053-61 8 The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Eng) J Med 1987; 316:1429-35 9 Kriett JM, Kaye ME The Registry of the International Society for Heart and Lung Transplantation: Eight official report 1991. J Heart Lung Transplant 1991; 10:491-98 10 Stevenson L~ Fowler MB, Schroeder JS, Stevenson WG, Dracup KA, Fond ~ Patients denied cardiac transplantation for non-medical criteria: a control group. J Am Coli Cardiol 1986; 7:9A 11 Stevenson L~ Fowler MB, Schroeder JS, Stevenson WG, Dracup KA, Fond ~ Poor survival of patients with idiopathic dilated cardiomyopathy considered too well for transplantation. Am J Med 1987; 83:871-76 12 Demakis JG, Proskey A, Rahimtoola SH, Jamil M, Sutton GC, Rosen KM, et al. The natural course of alcoholic cardiomyopathy. Ann Intern Med 1974; 80:293-97 13 Packer M, Medina N, Yushak M. Correction of dilutional hyponatremia in severe chronic heart failure by converting enzyme inhibition. Ann Intern Med 1984; 100:782-89 14 Stevenson L~ Dracup KA, Tillisch JH. Efficacy of medical therapy tailored for severe congestive heart failure in patients transferred for urgent cardiac transplantation. Am J Cardiol 1989; 63:461-64 15 Shirey EK, Proudfit WL, Hawk WA. Primary myocardial disease: correlation with clinical findings, angiographic and biopsy data. Am Heart J 1980; 99:198-207 16 Evans ~ Mannihen DL, Garrison L~ Maier AM. Donor availability as the primary detenninant of the future of heart transplantation. JAMA 1986; 255:1982-88

CHEST I 102 I 1 I JUL~

1992

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