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Ann Thorac Surg 2002;74:1075-1079
© 2002 The Society of Thoracic Surgeons
a Division of Thoracic and Cardiovascular Surgery, Hannover Medical School, Hannover, Germany
Accepted for publication May 29, 2002.
* Address reprint requests to Dr Wilhelmi, Division of Thoracic and Cardiovascular Surgery, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany
e-mail: wilhelmi{at}thg.mh-hannover.de
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Abstract |
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Methods. In a consecutive cohort of 65 patients (55 male, 54.6 ± 12.1 years at the time of transplantation), graft function was assessed by color Doppler echocardiography 12.5 ± 1.4 years after heart transplantation (10 to 15 years).
Results. Left atrial and ventricular dimensions were found in a normal range (LA 37.7 ± 8.9 mm, LV enddiastolic 45.6 ± 6.4 mm, 30 to 71 mm). Ejection fraction (EF) of 71 ± 11.7% and a fractional shortening of 35.3 ± 10.3% presented with normal values. Left ventricular mass (male 263.8 ± 111.4 g, female 373.0 ± 181.1 g) was slightly increased resulting in mild hypertrophy in women. Focused on right ventricular morphology, enlargement of both the right atrium and the right ventricle (RA 40.7 ± 11.8 mm, RV 37.4 ± 8.3 mm) was observed in the majority of the patients. Tricuspid valve insufficiency (> grade II) was present in 46 of 65 patients; 5 patients had previously undergone tricuspid valve replacement. Atrial filling waves were detectable in only 47 of 65 patients, thus, 28% of patients showed signs of LA-dysfunction.
Conclusions. More than 10 years post-HTX, cardiac grafts were characterized by normal left ventricular dimensions and ejection fraction. LA-dysfunction and RV-enlargement associated with tricuspid insufficiency were frequent findings, however, not associated with clinical signs of congestive heart failure in the majority of patients.
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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Mean age at the time of heart transplantation was 54.6 years with a standard deviation of 12.1 years. The youngest recipient was 30 years old and the oldest was 62. Mean follow-up period was 12.5 years (range 10 to 15 years). Indication for heart transplantation was dilated cardiomyopathy in 45 patients, coronary artery disease in 17, and other disorders (valve disease, endocardial fibrosis, and hypertrophic cardiomyopathie) in 3. All the patients received bi-atrial anastomoses for cardiac transplantation according to the technique of Shumway and colleagues [1].
Immunosuppression comprised a triple-drug regimen using cyclosporin A, prednisolone, and azathioprin. Target levels for cyclosporin A were 200 to 250 µg/l during the 1st year, 150 to 200 µg/l during the 2nd, and 100 to 150 µg/l thereafter (translated into monoclonal assay). Patients with compromised renal function were treated with adapted cyclosporine levels. All patients were continuously and closely monitored by our transplant outpatient clinic. For blood pressure control, patients were treated with ACE-inhibitors, beta-blockers, calcium channel antagonists, peripheral vasodilators, or combinations of these drugs. Frequency of examination was at least every 3 months beyond the 1st year after transplantation. All recipients underwent standard evaluation consisting of echocardiography, electrocardiography, and coronary angiography on an annual basis.
Echocardiographic measurements were performed using a Hewlett-Packard Sonos 5500 ultrasound (Hamburg, Germany) imaging system with a 2 to 5-MHz transducer from a standard window in the left lateral position. To measure atrial and ventricular dimensions, we used m-mode recordings in the parasternal long axis. Atrial measurements were made in the donor part of the atrium. Ejection fraction was calculated with the formula of Teichholz and coworkers [2], V = (7.0/2.4 + d) x D3 (V = volume, D = internal systolic ventricular dimension, d = internal enddiastolic ventricular dimension). Left ventricular mass (LVM) was calculated in grams from the m-mode measurements of left ventricular enddiastolic diameter (LVEDD), interventricular septum thickness (IVST), and left ventricular posterior wall thickness (PWT), using the formula modified by Devereux and Reichek [3]: LVM = 1.04 ([LVEDD + IVST + PWT]3 - LVEDD3) - 13.6. Valve competence was assessed by color Doppler echocardiography four-chamber view). Right ventricular ejection fraction was estimated visually and graded in impaired, or not impaired. Pulse wave Doppler technique over the mitral valve was used for evaluating left ventricular diastolic and atrial function. E-wave is defined by early inflow in the left ventricle, and A-wave by atrial systole.
Statistics
Statistical analysis was performed by using SPSS (Statistical Package for Social Sciences) for Windows, Version 7.5.2 (SPSS Inc, Chicago, IL). Continuous values are presented as mean ± standard deviation. Categorical variables were analyzed by the 
2 test. Comparison of values between patients regarding echocardiographic data was performed by a t test for independent samples. Values within the groups during the observation period were compared by paired t test. Differences were considered significant with a p-value of less than 0.05.
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Results |
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Morphology
Left ventricular dimensions were predominantly within the normal range. The mean left ventricular enddiastolic diameter was 45.6 ± 6.4 mm; mean left ventricular endsystolic diameter was 29.2 mm (numbers are detailed in Table 1).
Left atrial (LA) size presented within normal ranges with 37.7 ± 8.9 mm. Right heart dimensions were characterized by an enlargement of the right atrium (40.7 mm ± 11.8 mm) and the right ventricle (37.4 ± 8.3 mm) (Fig 1).
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Cardiac function
Normal graft function was demonstrated by echocardiographic quantification of left ventricular ejection fraction (71% ± 11.7%) (Fig 2).
Systolic function was completely normal in all but 2 patients, where ejection fractions of 34% and 49% were due to advanced allograft vasculopathy. Nineteen patients (29%) revealed an impaired right ventricular function; in 46 patients (71%), right ventricular function was normal. Mean fractional shortening (35.4% ± 10.3%) was observed within normal limits. The mean isovolumetric relaxation time was 88.2 ms ± 16.1 ms (range 60 ms to 140 ms). Furthermore, significant coronary stenoses (>50%) were found in 28 patients (43%) as assessed by coronary angiography.
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Normal mitral valve function was seen in 52 patients, 12 had mild mitral valve insufficiency, and 1 showed mitral valve regurgitation grade II. Competent function of the aortic valve was seen in 62 patients (95%), with mild aortic valve insufficiency in only 3 recipients, and no cases of degenerative stenosis.
An atrial filling wave was detectable in only 47 patients (72%). In the remaining 18 recipients with left atrial dysfunction, the underlying disease prior to HTX had been dilated cardiomyopathy in 17 and coronary artery disease in 1.
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Comment |
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However, despite these encouraging results, the later years after HTX are still accompanied by significant complications and deterioration of cardiac function [6]. In contrast to short-term heart transplant survivors where acute rejection and infection play a dominant role in mortality, the main causes for complications in long-term survivors are chronic rejection and the side effects of immunosuppressive medication [7]. In addition to these complications, reduced graft function may occur due to denervation of the graft and rhythm disturbances [8]. For these reasons, echocardiographic evaluation remains mandatory for a continuously growing number of patients following heart transplantation.
Echocardiographic assessment, in our patient cohort more than 10 years post-HTX, revealed as major findings: (1) a well-preserved left ventricular systolic function; (2) right ventricular and right atrial enlargement in the majority of patients; (3) intact left-sided heart valves as opposed to tricuspid regurgitation in the majority of grafts; and finally, (4) left atrial dysfunction as a frequent finding. In connection with the clinical status of the patients, these data can be considered a confirmation of heart transplantation to function as a successful and long-lasting treatment option for advanced heart failure.
Long-term survival and a consistent improvement in quality of life in patients surviving end-stage heart disease by transplantation [6, 7] is mainly based on a normalization of cardiac function. A mean ejection fraction of 62.8 ± 7.3% corresponding to a fractional shortening of 35.4 ± 10.3% in our patient cohort demonstrates that early and intermediate normalization of systolic contractility, as shown by earlier invasive and noninvasive approaches [9], remains constant over a 10 to 15-year period.
Comparable data were shown by De Campli and associates [10] in a 1995 study with 40 patients more than 10 years after heart transplantation. Invasive measurements from De Campli and colleagues showed relatively normal hemodynamic data and a well-preserved graft function in 26 patients.
All these data may serve as the major explanation for the favorable clinical status and exercise tolerance during long-term follow up after heart transplantation demonstrated independently by several groups [6, 7, 11]. Although severe left ventricular dysfunction is rare, in almost all cases caused by advanced cardiac allograft vasculopathy, there is some concern about an increasing diastolic dysfunction over time. Left ventricular hypertrophy due to a cyclosporine-induced arterial hypertension [9] and a progressive interstitial fibroses induced by ongoing cytokine activation [12, 13] are considered to be involved in pathogenesis. Noninvasive evaluation, especially by assessing the transmitral flow by echocardiography is limited by a left atrial dysfunction [14]. However, invasive studies suggest that this factor may contribute to a limited cardiac output in some patients and may become of increasing importance over time [15].
In contrast to normal left heart function parameters, enlargement of right atrium and ventricle appears to be a frequent observation. Several explanations have been discussed over the years [16]. These include a chronic pressure overload due to persistent pulmonary hypertension and a volume overload due to primary or secondary tricuspid insufficiency. As severe pulmonary hypertension is rare after HTX, tricuspid regurgitation, seen in more than 90% of patients, appears to be the most probable explanation. A geometric mismatch between donor and recipient atrial size, an inadequate dilated pericardial cavity [17], and biopsy-induced flail leaflets [18, 19] are involved in pathogenesis. Clinical symptoms related to right heart failure were unexpectedly rare in our cohort, but more frequently reported by others [16]. In 46 patients, the estimated right ventricle function was without impairment. As a consecutive series of tricuspid reconstructions failed, valve replacement may be considered the treatment of choice in symptomatic patients [20]. The subgroup of 5 patients with biological prostheses in tricuspid position reported here, recovered early after surgery with a stable course further on.
In comparison, left-sided heart valves presented in almost all patients with a normal morphology and function over the years. Degenerative aortic and mitral valve insufficiency or stenoses did not develop. Endocarditis, as might be expected due to immunosuppression, was not observed in this cohort and seems to be rare in heart transplant recipients in general [7, 21, 22].
As a final consideration, left atrial function has to be addressed. Especially utilizing the classic Shumway and coworkers’ [1] technique, an enlarged atrial filling volume, a potential mismatch between donor and recipient, as well as an ischemic or myopathic pathology in the recipient may contribute to left atrial dysfunction. Most of our patients with LA dysfunction had dilated cardiomyopathy. Despite all limitations in noninvasive detection of atrial function [14, 15], a lack of atrial filling waves demonstrates severe atrial dysfunction in at least 25% of the patients examined here.
In conclusion, this study demonstrates that heart transplantation results in normal left ventricular myocardial and valvular function, even more than 10 years postoperatively. Frequently, right heart function and tricuspid valve competence are impaired. However, symptomatic right heart failure is rare; tricuspid valve replacement might become necessary in these patients and can be performed successfully. Left atrial dysfunction can be observed and may be of clinical importance due to depressed hemodynamics and an increased risk of systemic embolism.
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  A. Koch, A. Remppis, T. J. Dengler, P. A. Schnabel, S. Hagl, and F.-U. Sack Influence of different implantation techniques on AV valve competence after orthotopic heart transplantation Eur. J. Cardiothorac. Surg., November 1, 2005; 28(5): 717 - 723. [Abstract] [Full Text] [PDF]
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 A. Lembcke, S. Dushe, S. Sonntag, C. Kloeters, C. N. H. Enzweiler, T. H. Wiese, B. Hamm, F.-X. Kleber, and W. F. Konertz Changes in right ventricular dimensions and performance after passive cardiac containment Ann. Thorac. Surg., September 1, 2004; 78(3): 900 - 905. [Abstract] [Full Text] [PDF]
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