American Heart Journal
Volume 141, Issue 2 , Page E7, February 2001

An angiotensin-converting enzyme inhibitor improves left ventricular systolic and diastolic function in transfusion-dependent patients with β-thalassemia major☆

  • Haralambos I. Karvounis, MD

      Affiliations

    • First Department of Cardiology, Aristotle University Thessaloniki, Greece
    • ,
  • Theodora A. Zaglavara, MD

      Affiliations

    • First Department of Cardiology, Aristotle University Thessaloniki, Greece
    • ,
  • Georgios E. Parharidis, MD

      Affiliations

    • First Department of Cardiology, Aristotle University Thessaloniki, Greece
    • ,
  • Ioannis G. Nouskas, MD

      Affiliations

    • First Department of Cardiology, Aristotle University Thessaloniki, Greece
    • ,
  • Eleni P. Hassapopoulou, MD

      Affiliations

    • Thalessemia Unit, American-Hellenic Educational Progressive Association General Hospital, Thessaloniki, Greece
    • ,
  • Konstantinos D. Gemitzis, MD

      Affiliations

    • First Department of Cardiology, Aristotle University Thessaloniki, Greece
    • ,
  • Georgios E. Louridas, MD, FCCP

      Affiliations

    • First Department of Cardiology, Aristotle University Thessaloniki, Greece

Received 7 August 2000; accepted 6 October 2000.

Article Outline

Abstract 

Background Cardiac complications are the major cause of death in patients with β-thalassemia major. The purpose of this study was to assess the impact of long-term treatment with the angiotensin-converting enzyme inhibitor enalapril on left ventricular (LV) performance, with an emphasis on diastolic LV function because diastolic dysfunction has been found to be an early event in an asymptomatic thalassemic population with only mild impairment of LV systolic function. Methods We used echocardiography to study the impact of treatment with oral enalapril on the evolution of standard M-mode and Doppler indices, along with a recently introduced Doppler index of combined systolic and diastolic LV performance. Results Patients were found to have significantly increased LV end-diastolic dimensions (LVEDD), LV end-systolic dimensions (LVESD), and left atrial dimensions and decreased LV fractional shortening (LVFS) compared with controls. After treatment with enalapril, LVESD decreased from 3.58 ± 0.3 cm to 3.23 ± 0.4 cm (P < .01) and LVFS increased from 32.6% ± 4.0% to 38.0% ± 3.1% (P < .001). Patients at baseline were found to have a significantly higher E-wave velocity, E/A ratio, and Doppler index compared with controls. The E-wave deceleration time was significantly shorter compared with that of controls. After treatment with enalapril, the E/A ratio decreased from 2.10 ± 0.42 to 1.50 ± 0.30 (P < .05), E-wave deceleration time increased from 0.12 ± 0.02 seconds to 0.15 ± 0.03 seconds (P < .01), and the Doppler index decreased from 0.46 ± 0.10 to 0.37 ± 0.14 (P < .05). Conclusions Enalapril was well tolerated in asymptomatic or minimally symptomatic patients with LV dysfunction resulting from β-thalassemia major. Echocardiographically we demonstrated significant improvement in LV systolic and diastolic function. Whether this translates to improved long-term prognosis and survival remains to be further evaluated. (Am Heart J 2001;141:e7.)

 

Cardiac complications are the major cause of death in patients with β-thalassemia major. In addition to chronic anemia, iron overloading is inevitable in patients with thalassemia because of repeated blood transfusions and enhanced gastrointestinal absorption. Although the contemporary management of these patients with hypertransfusion and chelation therapy has changed the natural history of the disease and improved survival,1 cardiac involvement remains the major cause of death in thalassemic patients.2 Left ventricular (LV) enlargement is a common finding in the late phase of thalassemia-related cardiomyopathy, but in its early stage it is considered to be a restrictive one. It is characterized by predominant diastolic dysfunction in the early stage and by systolic dysfunction in the late stage.3, 4 When cardiac impairment from iron deposition is severe enough to be clinically apparent, the disease process is considered to be advanced and the subsequent survival is brief.5

On the basis of the Studies of Left Ventricular Dysfunction (SOLVD) prevention trial, it has been suggested that angiotensin-converting enzyme (ACE) inhibitors should be used not only to treat but also to prevent heart failure development in patients with asymptomatic LV dysfunction resulting from either ischemic or nonischemic cardiomyopathy.6, 7, 8 Therefore the purpose of this study was to assess the impact of long-term treatment with ACE inhibitors on LV performance, with an emphasis on diastolic LV function, because diastolic dysfunction has been found to be an early event in an asymptomatic thalassemic population with only mild LV systolic dysfunction. We used echocardiography to study the impact of treatment with oral enalapril on the evolution of standard M-mode and Doppler indices, along with a recently introduced Doppler index of combined systolic and diastolic performance.9 This index has been found to be relatively simple to obtain, reproducible and independent of heart rate and blood pressure changes10 and to correlate well with overall cardiac function and clinical outcome in patients with cardiac amyloidosis.11

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Methods 

Study population 

Our study group consisted of 14 patients (6 male and 8 female, mean age 26 ± 5 years) with transfusion-dependent β-thalassemia major. All patients were from a transfusion program and maintained a pretransfusion hemoglobin concentration of at least 10 g/dL. All patients were receiving regular iron chelation treatment by means of subcutaneous desferrioxamine infusions. Patients were seen for a screening visit, at which they were selected for entry into the study if they met the following criteria: (1) absent or minimal heart failure symptoms (New York Heart Association class I), (2) absent or mild impairment of LV systolic function (with LV fractional shortening [LVFS] values >25%) along with a restrictive LV filling pattern defined as increased E-wave velocity and transmitral E-wave deceleration time [DT] values less than 130 milliseconds, (3) no current use of any cardiovascular medication, (4) a normal 12-lead electrocardiogram (ECG), (5) systolic blood pressure (BP) values in excess of 90 mm Hg, and (6) normal renal function and serum electrolyte concentrations.

Controls 

Fourteen healthy subjects (with a mean age of 24 ± 3 years) without clinical, ECG, and echocardiographic evidence of cardiovascular disease selected from among the hospital staff served as the control group. These subjects underwent echocardiographic evaluation at baseline and at the same follow-up intervals as the patients.

Study protocol 

The current study was approved by the institutional committee on human research, and appropriate informed consent was obtained from all subjects enrolled. Patients meeting all entry criteria were placed on treatment with oral enalapril 2.5 mg once daily, increased to 5.0 mg once daily within the first week of treatment. Clinical evaluation, along with BP measurements, renal function assessment, and serum electrolyte measurements, was performed at baseline and every week during the first month and was repeated along with echocardiographic evaluation at 3 and 6 months of therapy.

All echocardiographic measurements were done within 2 days from the last transfusion, and arterial BP was measured by cuff sphygmomanometry at the time of the echocardiographic evaluation.

Echocardiographic measurements 

A commercially available ultrasound system (Sigma Iris 440CFM, Kontron Instruments) with a 2.5-MHz transducer was used for all studies, and images were stored on an sVHS videotape simultaneously with the ECG. Data analysis was performed off-line with use of a commercially available software system by a single observer blinded to the clinical information. All patients were in sinus rhythm, and all measurements were done at rest. In each subject 5 consecutive cardiac cycles with the best possible signal-to-noise ratio were averaged for the Doppler measurements. The parasternal long-axis view at the papillary muscle level was used to obtain the following M-mode measurements: LV end-systolic (LVESD) and end-diastolic (LVEDD) dimensions, ventricular septal thickness, posterior wall thickness (PWT), and the dimensions of the left atrium (LA). LVFS was calculated as LVEDD – LVESD/LVEDD.

The LV inflow velocities were calculated from the apical 4-chamber view with the pulsed-wave Doppler sample volume at the tips of the mitral leaflets.12 The LV outflow velocities were measured from the apical 5-chamber view. The following measurements were obtained: (1) the peak early filling velocity (E wave), (2) the DT of the E-wave velocity, measured as the interval between the peak E velocity and the intersection of the deceleration of flow with the baseline, (3) the peak flow velocity during atrial contraction (A wave), (4) the ratio between the early and late peaks of flow velocity (E/A), (5) the interval from the cessation to the onset of mitral inflow (a), and (6) the LV ejection time measured as the duration of the aortic flow profile (b). The index of combined LV systolic and diastolic function (the sum of LV isovolumic contraction time and LV isovolumic relaxation time divided by LV ejection time) was calculated as (a – b)/b.9, 10, 11

Statistical analysis 

All values are expressed as the mean ± SD. Comparison of patient parameters before and after treatment with enalapril was made by use of the Student t test for paired observations. The same test was used to analyze measurement reproducibility. The unpaired Student t test was used for comparisons between patients and controls. A P value of <.05 was considered statistically significant.

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Results 

Treatment with enalapril was well tolerated in all patients and no side effects were reported. There was no significant difference in heart rate and BP between controls and patients or between patients before and after treatment with enalapril (Tables I and II). Measurement reproducibility was excellent for M-mode measurements (P = .896) and good for Doppler measurements (P = 0.762).

Table I. Clinical and 2-dimensional echocardiographic findings in control subjects and in patients before treatment with enalapril
Controls (n = 14)Patients (n = 14) at baselineStatistical significance
Age (y)22 ± 426 ± 5NA
Sex (male/female)6:86:8NA
HR (beats/min)77 ± 878 ± 11NS
Systolic BP (mm Hg)112 ± 9116 ± 13NS
Diastolic BP (mm Hg)76 ± 581 ± 9NS
LVEDD (cm)4.9 ± 0.45.4 ± 0.4P < .02
LVESD (cm)3.01 ± 0.33.58 ± 0.3P < .001
PWT (cm)0.81 ± 0.120.86 ± 0.12NS
IVS (cm)0.8 ± 0.10.92 ± 0.17NS
LA dimensions (cm)3.02 ± 0.363.6 ± 0.4P < .005
FS (%)38.9 ± 2.732.6 ± 3.4P < .001

NA, Not applicable; HR, heart rate; NS, not significant; IVS, interventricular septum.

Table II. Clinical and 2-dimensional echocardiographic findings in patients before and after 6 months of treatment with enalapril
Patients (n = 14) at baselinePatients (n = 14) after ACE-IStatistical significance
Age (y)26 ± 5NA
Sex (male/female)6:8NA
HR (beats/min)78 ± 1175 ± 11NS
Systolic BP116 ± 13113 ± 5NS
Diastolic BP81 ± 971 ± 7NS
LVEDD (cm)5.4 ± 0.45.2 ± 0.6NS
LVESD (cm)3.58 ± 0.33.23 ± 0.4P < .01
PWT (cm)0.86 ± 0.120.85 ± 0.12NS
IVS (cm)0.92 ± 0.170.93 ± 0.17NS
LA dimensions3.6 ± 0.43.49 ± 0.5NS
LVFS (%)32.6 ± 3.438.0 ± 3.1P < .001

NA, Not applicable; HR, heart rate; NS, not significant; IVS, interventricular septum.

M-mode measurements 

Patients were found to have significantly increased LVEDD, LVESD, and LA dimensions and decreased LVFS values compared with apparently healthy controls (Table I). After treatment with enalapril, LVESD decreased from 3.58 ± 0.3 cm to 3.23 ± 0.4 cm (P < .01) and LVFS values increased from 32.6% ± 4.0% to 38.0% ± 3.1% (P < .001) (Table II). No significant changes were noted in the other M-mode parameters measured. No significant change was noted between repeated measurements in the control group.

Doppler measurements 

Patients at baseline were found to have significantly higher E-wave velocity, E/A ratio, and Doppler index values compared with control subjects. The E-wave DT was significantly shorter compared with controls (Table III).

Table III. Doppler echocardiographic measurements in controls and in patients before treatment with enalapril
Controls (n = 14)Patients (n = 14) at baselineStatistical significance
E wave (m/sec)0.67 ± 0.130.91 ± 0.12P < .05
A wave (m/sec)0.48 ± 0.100.56 ± 0.14NS
E/A1.50 ± 0.302.10 ± 0.42P < .05
DT (sec)0.16 ± 0.020.12 ± 0.01P < .005
Index0.35 ± 0.060.46 ± 0.10P < .05

NS, Not significant.

After treatment with enalapril, E/A ratio values decreased from 2.10 ± 0.42 to 1.50 ± 0.30 (P < .05), E wave DT values increased from 0.12 ± 0.02 seconds to 0.15 ± 0.03 seconds (P < .01), and the Doppler index values decreased from 0.46 ± 0.10 to 0.37 ± 0.14 (P < .05) (Table IV).
Table IV. Doppler echocardiographic measurements in patients before and after 6 months of treatment with enalapril
Patients (n = 14) at baselinePatients (n = 14) after ACE-IStatistical significance
E wave (m/sec)0.91 ± 0.120.78 ± 0.20NS
A wave (m/sec)0.56 ± 0.140.58 ± 0.10NS
E/A2.10 ± 0.421.50 ± 0.30P < .05
DT (sec)0.12 ± 0.010.15 ± 0.03P < .01
Index0.46 ± 0.100.37 ± 0.14P < .05

NS, Not significant.

No significant changes were noted in the other Doppler parameters measured. No significant change was noted between repeated measurements in the control group.

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Discussion 

Most studies with ACE inhibitors in either symptomatic or asymptomatic LV dysfunction have mainly focused on the favorable effects of these compounds on LV systolic performance and ventricular remodeling.13, 14, 15 The hemodynamic benefits of ACE inhibitor therapy are documented by reduction of preload and afterload and improved ventricular performance, expressed as decreased LV dimensions and increased LV ejection fraction. In the current study both end-systolic and end-diastolic LV dimensions decreased with enalapril; however, only the decrease in end-systolic dimensions was statistically significant, leading to a significant improvement in LVFS values. A possible explanation for the insignificant decrease in LVEDD values is that, in addition to myocardial dysfunction from iron deposition, there is a significant volume overload from chronic anemia in these patients.16, 17

A restrictive diastolic filling pattern (ie, increased E-wave velocity along with a short deceleration time) is a common and early finding in thalassemic cardiomyopathy,3 usually preceding systolic dysfunction. In contrast to most forms of heart failure, in which a restrictive filling pattern is a finding of advanced systolic dysfunction and reflects increased LV diastolic pressures,18, 19 it reflects an increase in LV stiffness in the early stages of thalassemic cardiomyopathy.3, 20 In the current study, after 6 months of treatment with enalapril, the initially restrictive filling pattern was reversed in all patients. Additionally, the initially higher values of the Doppler index of overall LV performance (combining isovolumic contraction, isovolumic relaxation, and ejection time intervals) decreased to values similar to those obtained in the control group.

Several studies have shown that reversal of an initially restrictive filling pattern after long-term optimal therapy correlates with changes in pulmonary wedge pressure21 and predicts a more favorable outcome in patients with congestive heart failure resulting from idiopathic dilated18 or ischemic cardiomyopathy.19, 21 However, the patients included in these studies had advanced systolic dysfunction in contrast to our patients, who had only mild systolic impairment. The Doppler index of combined systolic and diastolic LV performance has been found to predict clinical outcome in patients with cardiac amyloidosis,11 but its prognostic significance in patients with thalassemic cardiomyopathy remains unknown.

The mechanism by which enalapril treatment improved diastolic LV function in our patients is unclear. Previous studies have demonstrated that LV filling is load dependent and that a decrease in preload decreases both E-wave velocity and E/A ratio and probably prolongs DT.22 Apart from preload reduction, enalapril may improve diastolic LV function by reducing myocardial fibrosis23, 24 or by protecting against iron-induced free radical injury.25, 26

Study limitations 

Cardiopulmonary exercise or other functional tests were not performed to assess exercise tolerance and possible functional improvement after treatment because the population studied was asymptomatic or only minimally symptomatic.

Although the pulmonary venous flow patterns were recorded in the majority of patients, the data were not used in this analysis because the significance of pulmonary venous flow patterns in young individuals is still controversial.27, 28

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Conclusions and clinical implications 

Enalapril was well tolerated in asymptomatic or minimally symptomatic patients with LV dysfunction resulting from β-thalassemia major. Echocardiography demonstrated significant improvement in LV systolic performance with reduced LVESD and increased LVFS after 6 months of treatment. Additionally, LV diastolic function was improved with reversal of an initially restrictive filling pattern and normalization of an initially increased Doppler index of overall LV performance. Whether this translates to improved long-term prognosis and survival remains to be further evaluated.

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References 

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☆ Reprint requests: H. I. Karvounis, MD, 101, Egnatia St, 54635 Thessaloniki, Greece. E-mail: jnouskas@hol.gr

PII: S0002-8703(01)66125-8

doi:10.1067/mhj.2001.112090

American Heart Journal
Volume 141, Issue 2 , Page E7, February 2001

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