Increase in systolic blood pressure during exercise testing after heart transplantation: correlation with the clinical condition and ventricular function assessed by dobutamine stress echocardiography

Abstracts

OBJETIVO: Em pacientes submetidos a transplante cardíaco (TxC) descreve-se redução da elevação da pressão arterial durante o teste ergométrico (TE). Este fenômeno, cuja origem é desconhecida, ocorre em freqüência e intensidade variáveis. O objetivo deste estudo foi verificar a relação entre o incremento da pressão arterial sistólica (deltaPAS) e aspectos clínicos, bem como as variáveis aferidas no TE e ecocardiograma sob estresse pela dobutamina (EED), em pacientes na fase tardia após TxC. MÉTODOS: Quarenta e cinco homens, 49,04±10,19 anos, 40,91±27,46 meses pós-TxC submeteram-se a avaliação clínica, TE e EED . Avaliou-se o índice de contratilidade segmentar e a fração de ejeção de ventrículo esquerdo. Consideraram-se anormais deltaPAS<35mmHg no TE (SBC,1995). RESULTADOS: Não houve correlação significativa entre deltaPAS e o tempo de evolução do transplante, tempo de isquemia do enxerto, antecedentes de rejeição, dose de diltiazem, consumo de oxigênio estimado, fração de ejeção e índice de contratilidade segmentar. O deltaPAS foi normal em 17 casos (Grupo I) e anormal em 28 pacientes (Grupo II). Não houve diferenças significativas entre os pacientes de ambos os grupos em relação aos aspectos clínicos e aos resultados do TE e EED. CONCLUSÃO: Ao contrário de outras populações, os autores não detectaram correlações entre deltaPAS e o quadro clínico e a função ventricular esquerda em pacientes com TxC. Os fatores associados à redução do deltaPAS no TE pós-TxC permanecem desconhecidos.

Transplante cardíaco; teste ergométrico; ecocardiograma

ORIGINAL ARTICLE

Increase in systolic blood pressure during exercise testing after heart transplantation: correlation with the clinical condition and ventricular function assessed by dobutamine stress echocardiography

Ana Fátima Salles; Cristiano Vieira Machado; Adriana Cordovil; Wagner Aparecido Leite; Valdir Ambrósio Moisés; Dirceu Rodrigues de Almeida; Antonio Carlos Camargo Carvalho; Japy Angelini Oliveira Filho

Universidade Federal de São Paulo - UNIFESP-EPM, São Paulo, SP, Brazil

^{Mailing Address}

ABSTRACT

OBJECTIVE: Patients who underwent heart transplantation (HTX) experience a reduction in the elevation that is usual in systolic blood pressure during exercise testing. Of unknown origin, this phenomenon varies in frequency and intensity. The aim of this study was to analyze the relationship between systolic blood pressure increase (delta SBP) and clinical aspects, as well as variables measured during exercise testing (ET) and dobutamine stress echocardiography (DSE) in patients in the late post-transplantation course.

METHODS: Forty-five men, mean age 49.04 ± 10.19, underwent clinical assessment, ET and DSE 40.91 ± 27.46 months after heart transplantation. Left ventricular wall motion score index and ejection fraction were assessed. Delta SBP < 35mmHg during ET was considered abnormal (SBC,1995).

RESULTS: No significant correlation was found between delta SBP and post-transplantation time, graft ischemic time, history of rejection, diltiazem dosage, oxygen uptake, ejection fraction, and wall motion score index (WMSI). Delta SBP was normal in 17 patients (Group I) and abnormal in 28 (Group II). Patients of both groups did not differ significantly in regard to clinical features and ET and DSE results.

CONCLUSION: Unlike other populations, no correlation was found between delta SBP during exercise testing and clinical condition or left ventricular function in heart transplant patients. Pathophysiological factors associated with delta SBP reduction during exercise testing remain unknown.

Key words: Heart transplantation, exercise testing, echocardiogram.

Systolic blood pressure elevation (delta SBP) during exercise testing (ET) has been related to left ventricular (LV) performance¹. In LV contractile dysfunction cases caused by ischemia or LV outflow tract obstruction, lower delta SBP values have been described¹. In the early and late post-transplantation (HTX) course, a depressed response in SBP^2-6 and mean BP^7-9 during ET has been observed. In an analysis of consecutive ET performed after heart transplantation showed that 69% of the heart recipients showed a depressed response of SBP during exercise testing¹⁰; delta SBP < 35mmHg was considered abnormal (SBC,1995)¹¹. The cause of SBP depressed response during ET after heart transplantation is still unclear⁷. It may be associated with graft vascular disease, one of the frequent causes of mortality among heart recipient survivors¹².

The aim of this study was to determine indicators of attenuated behavior of SBP during ET in male patients who underwent heart transplantation using clinical variables and parameters derived from ET and DSE.

Methods

Forty-five men, mean age 49.04 ± 10.19, were studied 40.91 ± 27.46 months after heart transplantation. Causes for transplantation were: idiopathic dilated cardiomyopathy (40%), chronic Chagas cardiomyopathy (33%), chronic ischemic cardiomyopathy (25%), and hypertensive cardiomyopathy (2%). Study patients were in NYHA functional class I (n = 43) and II (n = 2) and using cyclosporine A, azathioprine, prednisone, anti-hypertensive, lipid-lowering, and hypoglycemic drugs regularly. No patient showed rejection episodes exceeding grade 3A (International Society Heart Lung Transplantation) for at least two months. Mean graft ischemic time was 114.24 ± 29.73 minutes.

Symptom-limited exercise treadmill tests (TRACKMASTER TM 500-E) were conducted according to the Bruce protocol with a 13-lead ECG recording (TEB-APEX 2000). Systolic blood pressure (SBP) was measured at phase I of Korotkoff sounds and diastolic blood pressure (DBP) was measured at phase V, using a mercury sphygmomanometer. Oxygen uptake (VO₂) was estimated by regression equation¹³. Functional Aerobic Impairment (FAI) was defined by the following formula: FAI = (predicted VO₂ max – measured VO₂max) / predicted VO₂ max x 10². FAI values between – 27% to + 26% were considered normal¹. Exercise test results were analyzed according to criteria established by the Brazilian Society of Cardiology¹¹.

During dobutamine stress echocardiography (Ultramark 9-HDI, ATL), intravenous dobutamine was infused with or without atropine¹⁴. Regional LV contractility was evaluated by using the 16-segment model¹⁵, and the mean score was considered as the wall motion score index (WMSI)¹⁵. Left ventricular ejection fraction (EF) was determined by Simpson's method, both at rest and at peak infusion (Image Vue^TM DCR^TM, Nova Microsonics). Resting EF values above 0.55 were regarded as normal¹⁵. No reference values for EF at peak dobutamine infusion are reported in the literature

All procedures (clinical evaluation, ET, and DSE) were performed by independent observers.

The correlation between delta SBP and the following variables were analyzed: post-transplantation time, graft ischemic time, diltiazem dosage, VO₂max, resting EF, peak EF, delta EF, and % delta EF. Subsequently, patients were distributed into two groups: Group I - normal delta SBP (n = 17) and Group II - abnormal delta SBP (n = 28), so that possible markers of attenuated SBP responses between clinical variables and parameters measured by ET and DSE could be studied.

Pearson's correlation coefficient and multiple linear regressions were used to evaluate the linear relationship between delta SBP and selected variables. The Student's t-test, Fisher's exact test, and Pearson's chi-square test with Yates' correction were used to compare groups I and II. The paired t test and McNemar's test were applied to compare resting and peak values. P values < 0.05 were considered statistically significant.

The protocol was approved by the Institutional Research Ethics Committee, and all patients signed an informed consent before entering the study.

Results

No significant linear correlation was found between delta SBP and post-transplantation time, graft ischemic time, diltiazem dosage, VO₂max, resting EF, peak EF, and EF variation in absolute and relative values (Tab. 1).

The combined analysis of 10 variables, for which multiple linear regression (resting EF, peak EF, and % EF, WMSI at rest, WMSI at peak infusion, post-transplantation time, graft ischemic time, history of rejection episodes > 3 A, diltiazem dosage, VO₂max) were used, showed that no variable, at the 10% significance level, influenced delta SBP values (Tab. 2).

No significant differences were found between groups I and II regarding age, body weight, height, post-transplantation time, graft ischemic time, arterial hypertension, dyslipidemia and obesity, history of rejection > 3 A, and use of prednisone, statins or diltiazem (Tab. 3).

Exercise test results are described in Table 4.Groups I and II showed similar resting heart rate (HR), resting BP, % of predicted HRmax, VO₂ max, FAI, endurance time (p = NS). Exercise testing was considered ischemic in two patients from group I and one patient from group II. SBP values at exercise peak and delta SBP were significantly lower in group II (p < 0.001).

DSE results are presented in Tables 5 and 6. Both groups underwent stress with the same dose of dobutamine and reached equivalent percentages of predicted HRmax. One patient from group I and four patients from group II required atropine co-administration.

There were no significant differences between groups with respect to: [1] WMSI and EF values at rest and at peak infusion; [2] abnormal WMSI at rest and at peak infusion; [3] presence of myocardial ischemia.

Discussion

Blood pressure is governed by a complex mechanism involving hemodynamic, neural, and hormonal factors. Its determinants are cardiac output and peripheral resistance. SBP is primarily related to factors influencing ventricular performance, namely contractility, the degree to which myocardial fibers are stretched (Frank-Starling principle), blood volume, resistance to blood ejection (afterload), and heart rate.

The SBP rises during exercise, showing a 50% increase over its baseline value at maximal exercise¹⁶. In this study, 62% of the patients experienced a depressed response in SBP during ET performed at late post-transplantation course. It has been suggested that abnormal delta SPB during ET is associated with reduced inotropic reserve secondary to changes in contractility caused by coronary disease, Chagas cardiomyopathy, hypertensive cardiomyopathy, dilated cardiomyopathy, and other heart diseases^1,17-19.

Our results showed no correlation between abnormal delta SBP and post-transplantation time. On average, patients had undergone heart transplantation more than three years earlier and, thereby, were subject to graft vascular disease.

Graft vascular disease is the major cause of death after the first year of heart transplantation²⁰. Dobutamine stress echocardiography has emerged as a promising non-invasive examination for detecting this condition²¹, with sensitivity of 67% to 100%, specificity of 55% to 89.5%, negative predictive value of 90% to 100% and positive predictive value of 33% to 76%^22-25. Graft vascular disease may cause changes in LV contractility, affecting delta SBP. The association between delta SBP and ischemia secondary to graft vascular disease is yet to be established. Myocardial ischemia incidence in groups I and II by DSE was 6% and 21%, respectively; however, no statistical significance was found between these values (p = 0.227), even though ischemia was three times higher in group II. This lack of significance may be related to the number of patients studied. Nor was significant difference found between groups I and II regarding, respectively, EF decrease at peak DSE (35.3% vs 17.8%) and mean EF increase during DSE (6.06 ± 16.03 vs 13.83 ± 17.74).

Rejection episodes are common after heart transplantation and, if repeated, may cause fibrosis and a decrease in ventricular cavity size⁹. Under dobutamine stress, Bellotti et al. reported normal contractility in heart transplant recipients in whom there was no rejection. In the presence of rejection, contractility was reduced²⁶. Our series did not corroborate these findings, since history of rejection was similar in groups I and II (23% vs 18%, p = NS). Among the nine patients with history of rejection, only three showed changes in contractility, two from Group I (normal delta SBP) and one from Group II (abnormal delta SBP). No case of ventricular fibrosis or reduction in ventricular cavity was identified.

Some authors have attributed the enhanced pressure response to exercise to a late sympathetic reinnervation. Wilson et al described a trend to increased delta SBP during late follow-up of patients with evidence of marked reinnervation after heart transplantation²⁷.

Abnormal delta SBP values might be influenced by LV stiffness and dysfunction secondary to ventricular ischemia caused during cold preservation of the graft^28,29. In our series, mean graft ischemic time was 114 minutes and was not correlated with abnormal delta SBP. According to Kao et al, it is unlikely that two hours of cold ischemia would cause changes in the graft capable of persisting up to 16 months post-transplantation⁸.

Diltiazem hydrochloride has been frequently used for BP control after heart transplantation. In our series, 28 (62.2%) patients took diltiazem regularly at doses ranging from 60 to 240 mg/day. Drug dosage did not correlate with delta SBP during exercise testing. Both the percentage of patients on diltiazem and the dose used were similar in both groups.

No correlation was found between abnormal delta SBP and VO₂max. According to the Fick principle, VO₂ varies with HR, stroke volume, and arteriovenous oxygen difference. SBP is a function of HR, stroke volume, contractility, preload and afterload. Therefore, it would be possible to detect abnormal delta SBP in the presence of the decreased VO₂max values. Douard et al³⁰ found a significant correlation between SBP peak values and VO₂max. In our study, not only was this relationship not observed, but groups I and II reached equal VO₂max values. These results may have been affected by the estimated values used, calculated from formulas that were perhaps inadequate for transplant patients. Actually, the use of direct measurements of VO₂max in cardiopulmonary tests would have been more appropriate.

Overall, LV systolic performance after heart transplantation has been shown to be satisfactory at rest and during exercise. Most studies have reported normal LV values at rest and at exercise peak, during both early and late follow-up^8,9,31-37. In our study, LV systolic function, assessed by the WMSI and EF, showed no correlation with abnormal delta SBP. WMSI and EF values were similar in patients of both groups. Our results were corroborated by other authors. Pflugfelder at al found no correlation between peak EF and peak BP during exercise in patients after thirteen months of transplantation³².

Other clinical, ergometric, and echocardiographic measurements also failed to characterize the abnormal delta SBP group. Groups I and II shared the same clinical features, and their results were similar on ET and DSE.

Limitations- Our study has some limitations, [1] namely, the small number of patients in groups I and II; [2] and population heterogeneity regarding different etiologies.

Conclusions

Unlike other populations, the authors found no correlation between abnormal delta SBP and clinical data plus left ventricular function in heart recipients at late post-transplantation course. A significant number of these patients progress to attenuated delta SBP during ET. The pathophysiology of this behavior remains unknown. This phenomenon is probably multifactorial in origin, reflecting a distinctive characteristic of transplanted patients.

References

Manuscript received April 15, 2004; revised manuscript received May 1, 2006; accepted May 5, 2006.

• 1. Bruce RA. Exercise testing of evaluation of ventricular function. N Engl J Med 1977; 296:671-5.
• 2. Hidalgo R, Alegria E, Castello R, et al. Stress testing in patients one year after orthotopic cardiac transplantation. Angiology 1989; 40(7): 650-5.
• 3. Braith RW, Wood CE, Limacher MC, et al. Abnormal neuroendocrine responses during exercise in heart transplant recipients. Circulation 1992; 86: 1453-63.
• 4. Rudas L, Pflugfelder PW, Kostuk WJ. Hemodynamic observations following orthotopic cardiac transplantation: hemodynamic responses to upright exercise at 1 year. Acta Physiol Hung 1992; 79(1):49-56.
• 5. Martin TW, Gaucher J, Pupa LE, Seaworth JF. Response to upright exercise after cardiac transplantation. Clin Cardiol 1994; 17:292-300.
• 6. Notarius CF, Levy RD, Tully A, Fitchett D, Magder S. Cardiac versus noncardiac limits to exercise after heart transplantation. Am Heart J 1998; 135:339-48.
• 7. Marzo KP, Wilson JR, Mancini DM. Effects of cardiac transplantation on ventilatory response to exercise. Am J Cardiol 1992; 69:547-53.
• 8. Kao AC, Trigt PV, Shaeffer-McCall GS, et al. Central and peripheral limitations to upright exercise in untrained cardiac transplant recipients. Circulation 1994; 89:2605-15.
• 9. Kao AC, Trigt PV, Shaeffer-McCall GS, et al. Allograft diastolic dysfunction and chronotropic incompetence limit cardiac output response to exercise two to six years after heart transplantation. J. Heart Lung Transplant 1995; 14:11-22.
• 10. Salles AF, Machado CV, Leite WA, et al. Teste ergométrico em transplantados: resposta inotrópica deprimida. Arq Bras Cardiol 1999; 73(supl.VI):58.
• 11. Mastrocolla LE, Brito AX, Brito FS, et al. Consenso Nacional de Ergometria. Arq Bras Cardiol 1995; 65(2): 189-211.
• 12. Chomette G, Auriol M, Cabrol C. Chronic rejection in human heart transplantation. J. Heart Transplant 1988; 7:292.
• 13. Bruce RA, Kusumi F, Hosmer D. Maximal oxygen intake and nomographic assessment of functional aerobic impairment in cardiovascular disease. Am Heart J 1973; 85:546-62.
• 14. Mcneill A, Fioretti PM, El Said SM, et al. Enhanced sensitivity for detection of coronary artery disease by addition of atropine to dobutamine stress echocardiography. Am J Cardiol. 1992; 70:41-6.
• 15. American Society of Echocardiography Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echo 1989; 2(5):358-67.
• 16. Aloan L. Hemodinâmica e angiocardiografia. Obtenção de dados, interpretação e aplicações clínicas. São Paulo: Ed. Atheneu, 1982: 58p.
• 17. Araujo WB. Ergometria e Cardiologia Desportiva. Rio de Janeiro: MEDSI, 1986: 149p.
• 18. Froelicher VF. Exercise and the Heart. Clinical Concepts. Chicago: Year Book, 1987.
• 19. Myers J, Froelicher VF. Teste de esforço e reabilitação cardíaca. Clin Cardiol 1993; 2:203-18.
• 20. Chomette G, Auriol M, Cabrol C. Chronic rejection in human heart transplantation. J Heart Transplant 1998; 7: 292.
• 21. Akosah KO, Mohanty PK. Role of dobutamine stress echocardiography in heart transplant patients. Chest 1998; 113:809-15.
• 22. Akosah KO, Mohanty PK, Funai JT, et al. Noninvasive detection of transplant coronary artery disease by dobutamine stress echocardiography. J Heart Lung Transplant 1994; 13:1024-38.
• 23. Derumeaux G, Redonnet M, Mouton-Schleifer D, et al. Dobutamine stress echocardiography in orthotopic heart transplant recipients. J Am Coll Cardiol 1995; 25:1665-72.
• 24. Spes CH, Klauss V, Rieber J, et al. Functional and morphological findings in heart transplant recipients with a normal coronary angiogram: an analysis by dobutamine stress echocardiography, intracoronary doppler and intravascular ultrasound. J Heart Lung Transplant 1999;18:391-8.
• 25. Machado CV. Valor da ecocardiografia sob estresse com dobutamina e da cintilografia de perfusão miocárdica com tetrofosmin no diagnóstico da doença vascular do enxerto pós-transplante cardíaco. Tese Doutorado. São Paulo, 2000. Escola Paulista Medicina/Unifesp.
• 26. Bellotti G, Moraes AV, Bocchi EA, et al. Efeitos da rejeição na reserva de contratilidade do enxerto após o transplante cardíaco. Arq Bras Cardiol 1996; 67: 5-9.
• 27. Wilson RF, Johnson TH, Haidet GC, Kubo SH, Mianuelli M. Sympathetic reinnervation of the sinus node exercise hemodynamics after cardiac transplantation. Circulation 2000; 101:2727-33.
• 28. Marti V, Ballester M, Auge JM, Obrador D, Moya C, Caralps-Riera J M. Donor and recipient determinants of fatal and nonfatal cardiac dysfunction during the first week after orthotopic heart transplantation. Transplant Proc 1992; 24: 16-9.
• 29. Begona JA, Gundry SR, Razzouk AJ, Boucek MM, Bailey LL. Prolonged ischemic times in pediatric heart transplantation: early and late results. Transplant Proc 1993; 25: 1645-8.
• 30. Douard H, Parrens E, Billes MA, Labbe L, Baudet E, Broustet JP. Predictive factors of maximal aerobic capacity after cardiac transplantation. Eur Heart J 1997; 18: 1823-8.
• 31. Pflugfelder PW, Purves PD, Mckenzie FN, Kostuk WJ. Cardiac dynamics during supine exercise in cyclosporine-treated orthotopic heart transplant recipients: assessment by radionuclide angiography. J Am Coll Cardiol 1987; 10: 336-41.
• 32. Pflugfelder PW, Purves PD, Menkis AH, Mckenzie FN, Kostuk WJ. Rest and exercise left ventricular ejection and filling characteristics following orthotopic cardiac transplantation. Can J Cardiol 1989; 5: 161-67.
• 33. Stevenson LW, Sietsema K, Tillisch JH, et al. Exercise capacity for survivors of cardiac transplantation or sustained medical therapy for stable failure. Circulation 1990; 81: 78-85.
• 34. Younis LT, Melin JA, Schoevaerdts JC, et al. Left ventricular systolic function and diastolic filling at rest and during upright exercise after orthotopic heart transplantation: comparison with young and aged subjects. J Heart Transplant 1990; 9: 683-92.
• 35. Murali S, Carell ES, Uretsky BF, Estrada-Quintero T, Tokarczyk TR, Cannon Y M. Determinants of exercise performance early and late after cardiac transplantation. Chest 1992; 102: S77.
• 36. Tischler MD, Lee RT, Plappert T, Mudge GH, Sutton MJ, Parker JD. Serial assessment of left ventricular function and mass after orthotopic heart transplantation: A 4 year longitudinal study. J Am Coll Cardiol 1992; 19: 60-6.
• 37. Ohar J, Osterloh J, Ahmed N, Miller L. Diffusing capacity decreases after heart transplantation. Chest 1993; 103: 857-61.

Publication Dates

• Publication in this collection
  06 Mar 2007
• Date of issue
  Nov 2006

History

• Received
  15 Apr 2004
• Reviewed
  01 May 2006
• Accepted
  09 May 2006