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Cardiac microvascular vasomotor response as a prognostic marker of left ventricular function in cardiac transplant recipients
ELSEVIER
Cardiac Microvascular Vasomotor Response as a Prognostic of Left Ventricular Function in Cardiac Transplant Recipients M. Weis, A. Hartmann,
H.G. Olbrich
T tation
HE long-term survival of patients after heart transplanis limited by the development of cardiac allograft vasculopathy (CAV).’ The lumina of the smaller intramyocardial branches are often occluded before those of the larger epicardial arteries and this results in small, multiple, stellate infarcts.’ To assess the degree to which transplant vascular sclerosis affects the resistance vessels, coronary blood flow measurement is useful. Several studies in transplant recipients suggest that resistance vessel function is altered at an early stage of the coronary disease process. 3,4 The left ventricular systolic function is relatively well preserved in patients without significant acute rejection5 but the importance of microvascular vasomotor (dys)function in the development of reduced left ventricular function has not been investigated. Therefore, it was the purpose of the present study to assess the relationship of coronary blood flow reserve (CFR) and subsequent changes in left ventricular systolic function to establish the clinical utility of coronary flow measurement to identify a distinct subset of patients in whom closer monitoring and aggressive risk factor modification may be indicated.
PATIENTS
AND
METHODS
Seventeen patients (47 t 15 yrs, 40 2 21 months transplantation)
were selected
after cardiac from a series of consecutive trans-
plant recipients according to predefined exclusion criteria graphic evidence of CAV, episode of acute rejection,
(angioarterial
hypertension unless treated adequately, and elevated left ventricular wall thickening). Immunosuppressive therapy was standardized and consisted of cyclosporine, prednisone, and azathioprine. Following the diagnostic catheterization procedure, endotheliumdependent (in response to 50 pg acetylcholine) and endotheliumindependent (in response to 0.48 mgikgi4min dipyridamole) CFR was measured using a Judkins-style 8F Doppler-Catheter. CFR was determined by the ratio of the maximal coronary flow index after medical stimulation to the basal flow index.3 The radionuclide ventriculography was performed within 1 month after coronary flow measurement and repeated 2 years later. Exercise was initiated at a work load of 25-50 W according to the clinical condition of the patient and was increased by 25 W every 3 min to the point of moderate to severe fatigue. Left ventricular ejection fraction and end-diastolic volume were determined with methods previously reported.’
0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
Transplantation
Marker
Proceedings, 29, 2573-2574
(1997)
RESULTS Coronary Flow Measurements
The endothelium-independent CFR, defined as the ratio of the maximal coronary flow index in response to dipyridamole, was 3.0 t 1.6. The endothelium-dependent CFR (the ratio of the maximal flow index) in response to ACh was 2.3 t 0.8. Radionuclide
Ventriculography
In 13 patients, ejection fraction at rest decreased, and in 4 patients ejection fraction at rest increased during follow up. In 12 patients, ejection fraction during exercise decreased, 1 patient showed no change, and in 4 patients, ejection fraction during maximal exercise increased during follow up. In the entire study group, resting ejection fraction decreased by -9 ? 2% (not significant; NS) and the maximal ejection fraction during exercise decreased by -7 of: 3% (NS). Correlation
Analysis
Ventricular
Function
Between
CFR and Changes
in Left
There was a significant correlation between CFR in response to dipyridamole and changes in ejection fraction at rest (r = 0.59; P < .Ol) and during exercise (r = 0.48; P < .OS) 24 months later. The CFR in response to acetylcholine showed a trend with a reduction of ejection fraction during exercise 24 months later. Patients with a CFR in response to dipyridamole <2.5 showed a significantly reduced ejection fraction during maximal exercise (-7 ? 5%) 24 months after the initial measurement compared to patients with a CFR >2.5 (percent change in ejection fraction during exercise 1.1 ? 5%; P = .003). The changes in resting ejection fraction did not reach statistical significance, but there was a conspicuous trend between an endotheliumindependent CFR in response to dipyridamole ~2.5 and a From the Medizinische Klinik IV, J.W. Goethe-University Medical Center, Frankfurt am Main (A.H., H.G.O.) and Medizinische Klinik I, University of Munich, Klinikum Grosshadern, Munich, Germany (M.W.). Address reprint requests to Dr Michael Weis, University of Munich, Klinikum Grosshadern, Medizinische Klinik I, Marchioninistrasse 15, D-81377 Munich, Germany.
0041-l 345/97/$17.00 PII SO041 -1345(97)00512-5
2573
WEIS, HARTMANN,
2574
greater loss of left ventricular function (change in resting ejection fraction -7.6 t- 6% versus ~ I .1 ? 7%; P = .07). DISCUSSION
CFR after cardiac transplantation is preserved in the first 2 years after cardiac transplantation, but is reduced after long-term follow up, even in the absence of flow-limiting epicardial stenoses3.” This observation might be attributed to structural changes of the myocardium as a consequence of subclinical rejection episodes and the development of left ventricular hypertrophy, or it may represent a manifestation of CAV affecting microvascular vessels. However, the consequences of a reduced CFR with respect to left ventricular function have never been investigated. The most important finding of the present study was that in cardiac transplant patients without angiographically visible CAV, a blunted CFR response after dipyridamole was associated with significant changes in ejection fraction at rest and during exercise 24 months after the initial measurement. Patients with a CFR to dipyridamole ~2.5 showed 24 months later a significant decline in ejection fraction during exercise compared to patients with a CFR >2.5. Importantly, there was no significant correlation between time posttransplant and tither CFR, or resting/exercise ejection fraction. The impaired CFR may lead to chronic left ventricular subendocardial ischemia and resultant impairment of left ventricular function.’ Indeed, experimental studies have shown that even small reductions in coronary blood flow can cause a
AND OLBRICH
decrease in regional ventricular function.” Therefore, rcduction in CFR, associated with exercise induced myocardial ischemia,’ may importantly contribute to the progresIn summary, of left ventricular dysfunction. sion endothelium-independent microvascular dysfunction has prognostic importance for deterioration of left ventricular function in cardiac transplant recipients without angiographically visible coronary artery lesions. These results reinforce the concept that microvascular and epicardial vessel disease after transplantation are two distinct entities with different functional consequences.’
REFERENCES 1. Weis M, Von Scheidt
W: Circulation
2. Neish AS, Loh E, Schoen 3. Hartmann 15:1486, 1994 4. Treasure 1992
A, Weis
M, Olbrich
CB, Vita JA. Ganz
5. Von Scheidt W, Ziegler Transplant 10342, 1991 6. Hartmann 20:146, 1993
A, Maul
7. Vekshtein 82:2068, 1990
VI, Alexander
8. Cianflone
D, Lanza
9. Zeiher AM, 91:2345, 1995
Krause
1907 (in press)
FJ: J Am Coil Cardiol HG,
P, et al: Circulation
U, Kemkes
FD, Huth
1992
Heart
J
X6:1156,
BM, et al: J Heart
Lung
A, et al: Eur J Nuclear
Med
RW, Ycung
GA, Maseri
19586,
et al: Em
AC. et al: Circulation
A: Eur Heart
T. Schachinger
J 16:S96, 1995
V, ct al: Circulation
Cardiac Microvascular Vasomotor Response as a Prognostic of Left Ventricular Function in Cardiac Transplant Recipients M. Weis, A. Hartmann,
H.G. Olbrich
T tation
HE long-term survival of patients after heart transplanis limited by the development of cardiac allograft vasculopathy (CAV).’ The lumina of the smaller intramyocardial branches are often occluded before those of the larger epicardial arteries and this results in small, multiple, stellate infarcts.’ To assess the degree to which transplant vascular sclerosis affects the resistance vessels, coronary blood flow measurement is useful. Several studies in transplant recipients suggest that resistance vessel function is altered at an early stage of the coronary disease process. 3,4 The left ventricular systolic function is relatively well preserved in patients without significant acute rejection5 but the importance of microvascular vasomotor (dys)function in the development of reduced left ventricular function has not been investigated. Therefore, it was the purpose of the present study to assess the relationship of coronary blood flow reserve (CFR) and subsequent changes in left ventricular systolic function to establish the clinical utility of coronary flow measurement to identify a distinct subset of patients in whom closer monitoring and aggressive risk factor modification may be indicated.
PATIENTS
AND
METHODS
Seventeen patients (47 t 15 yrs, 40 2 21 months transplantation)
were selected
after cardiac from a series of consecutive trans-
plant recipients according to predefined exclusion criteria graphic evidence of CAV, episode of acute rejection,
(angioarterial
hypertension unless treated adequately, and elevated left ventricular wall thickening). Immunosuppressive therapy was standardized and consisted of cyclosporine, prednisone, and azathioprine. Following the diagnostic catheterization procedure, endotheliumdependent (in response to 50 pg acetylcholine) and endotheliumindependent (in response to 0.48 mgikgi4min dipyridamole) CFR was measured using a Judkins-style 8F Doppler-Catheter. CFR was determined by the ratio of the maximal coronary flow index after medical stimulation to the basal flow index.3 The radionuclide ventriculography was performed within 1 month after coronary flow measurement and repeated 2 years later. Exercise was initiated at a work load of 25-50 W according to the clinical condition of the patient and was increased by 25 W every 3 min to the point of moderate to severe fatigue. Left ventricular ejection fraction and end-diastolic volume were determined with methods previously reported.’
0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
Transplantation
Marker
Proceedings, 29, 2573-2574
(1997)
RESULTS Coronary Flow Measurements
The endothelium-independent CFR, defined as the ratio of the maximal coronary flow index in response to dipyridamole, was 3.0 t 1.6. The endothelium-dependent CFR (the ratio of the maximal flow index) in response to ACh was 2.3 t 0.8. Radionuclide
Ventriculography
In 13 patients, ejection fraction at rest decreased, and in 4 patients ejection fraction at rest increased during follow up. In 12 patients, ejection fraction during exercise decreased, 1 patient showed no change, and in 4 patients, ejection fraction during maximal exercise increased during follow up. In the entire study group, resting ejection fraction decreased by -9 ? 2% (not significant; NS) and the maximal ejection fraction during exercise decreased by -7 of: 3% (NS). Correlation
Analysis
Ventricular
Function
Between
CFR and Changes
in Left
There was a significant correlation between CFR in response to dipyridamole and changes in ejection fraction at rest (r = 0.59; P < .Ol) and during exercise (r = 0.48; P < .OS) 24 months later. The CFR in response to acetylcholine showed a trend with a reduction of ejection fraction during exercise 24 months later. Patients with a CFR in response to dipyridamole <2.5 showed a significantly reduced ejection fraction during maximal exercise (-7 ? 5%) 24 months after the initial measurement compared to patients with a CFR >2.5 (percent change in ejection fraction during exercise 1.1 ? 5%; P = .003). The changes in resting ejection fraction did not reach statistical significance, but there was a conspicuous trend between an endotheliumindependent CFR in response to dipyridamole ~2.5 and a From the Medizinische Klinik IV, J.W. Goethe-University Medical Center, Frankfurt am Main (A.H., H.G.O.) and Medizinische Klinik I, University of Munich, Klinikum Grosshadern, Munich, Germany (M.W.). Address reprint requests to Dr Michael Weis, University of Munich, Klinikum Grosshadern, Medizinische Klinik I, Marchioninistrasse 15, D-81377 Munich, Germany.
0041-l 345/97/$17.00 PII SO041 -1345(97)00512-5
2573
WEIS, HARTMANN,
2574
greater loss of left ventricular function (change in resting ejection fraction -7.6 t- 6% versus ~ I .1 ? 7%; P = .07). DISCUSSION
CFR after cardiac transplantation is preserved in the first 2 years after cardiac transplantation, but is reduced after long-term follow up, even in the absence of flow-limiting epicardial stenoses3.” This observation might be attributed to structural changes of the myocardium as a consequence of subclinical rejection episodes and the development of left ventricular hypertrophy, or it may represent a manifestation of CAV affecting microvascular vessels. However, the consequences of a reduced CFR with respect to left ventricular function have never been investigated. The most important finding of the present study was that in cardiac transplant patients without angiographically visible CAV, a blunted CFR response after dipyridamole was associated with significant changes in ejection fraction at rest and during exercise 24 months after the initial measurement. Patients with a CFR to dipyridamole ~2.5 showed 24 months later a significant decline in ejection fraction during exercise compared to patients with a CFR >2.5. Importantly, there was no significant correlation between time posttransplant and tither CFR, or resting/exercise ejection fraction. The impaired CFR may lead to chronic left ventricular subendocardial ischemia and resultant impairment of left ventricular function.’ Indeed, experimental studies have shown that even small reductions in coronary blood flow can cause a
AND OLBRICH
decrease in regional ventricular function.” Therefore, rcduction in CFR, associated with exercise induced myocardial ischemia,’ may importantly contribute to the progresIn summary, of left ventricular dysfunction. sion endothelium-independent microvascular dysfunction has prognostic importance for deterioration of left ventricular function in cardiac transplant recipients without angiographically visible coronary artery lesions. These results reinforce the concept that microvascular and epicardial vessel disease after transplantation are two distinct entities with different functional consequences.’
REFERENCES 1. Weis M, Von Scheidt
W: Circulation
2. Neish AS, Loh E, Schoen 3. Hartmann 15:1486, 1994 4. Treasure 1992
A, Weis
M, Olbrich
CB, Vita JA. Ganz
5. Von Scheidt W, Ziegler Transplant 10342, 1991 6. Hartmann 20:146, 1993
A, Maul
7. Vekshtein 82:2068, 1990
VI, Alexander
8. Cianflone
D, Lanza
9. Zeiher AM, 91:2345, 1995
Krause
1907 (in press)
FJ: J Am Coil Cardiol HG,
P, et al: Circulation
U, Kemkes
FD, Huth
1992
Heart
J
X6:1156,
BM, et al: J Heart
Lung
A, et al: Eur J Nuclear
Med
RW, Ycung
GA, Maseri
19586,
et al: Em
AC. et al: Circulation
A: Eur Heart
T. Schachinger
J 16:S96, 1995
V, ct al: Circulation