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European Journal of Heart Failure 2005 7(4):490-497; doi:10.1016/j.ejheart.2004.06.005
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© 2005 European Society of Cardiology

Combined systolic and diastolic dysfunction in the presence of preserved left ventricular ejection fraction

Ian P. Clements*

Division of Cardiovascular Diseases and Internal Medicine Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States

* Tel.: +1 507 284 8917; Fax: +1 507 284 2107. E-mail address: lovejoy.margery{at}mayo.edu


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgment
 References
 
Background: Heart failure with preserved left ventricular ejection fraction (LVEF) suggests isolated diastolic dysfunction.

Aim: The purpose of this study was to determine if systolic and diastolic dysfunction occurred with preserved LVEF.

Methods: Equilibrium resting radionuclide ventriculograms from 439 patients with an LVEF ≥0.50 were used to determine LV peak filling rate (PFR) and peak ejection rate (PER) in end-diastolic volumes per second and LV end-systolic volume (ml). Patients with low-normal (n=147; range, 0.50–0.58; mean±S.D., 0.53±0.02), intermediate-normal (161, 0.59–0.64, 0.61±0.02), and high-normal (131, 0.65–0.94, 0.72±0.06) LVEF were compared.

Results: From low-normal to intermediate-normal to high-normal LVEF, LV end-systolic volume decreased (93±36, 71±33, 43±26, respectively, P<0.0001), PFR increased (2.31±0.74, 2.58±0.74, 3.15±0.94, P<0.0001), PER increased (–2.78±0.50, –3.13±0.47, –3.83±0.84, P<0.0001), the percentages of patients with abnormal PFR decreased (66, 56, 40, P<.0001), and the percentage with abnormal PER decreased (47, 14, 5, P<0.0001). Of 193 patients with preserved LVEF and abnormally low PFR, 65 (34%) had abnormally low PER.

Conclusions: The results indicate that a preserved LVEF was often associated with LV systolic dysfunction (enlarged LV end-systolic volume and low PER) and LV diastolic dysfunction (decreased PFR).

Key Words: Diastole • Radionuclide • Systole • Ventriculography

Received December 4, 2003; Revised April 6, 2004; Accepted June 29, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgment
 References
 
Symptomatic heart failure has been divided into two syndromes [1,2] on the basis of the left ventricular ejection fraction (LVEF). "Systolic heart failure" is defined as heart failure with a reduced LVEF, and "diastolic heart failure" is defined as heart failure with a preserved LVEF. Increasingly, diastolic heart failure is becoming a recognized clinical syndrome, with growing importance relevant to the total clinical burden of heart failure [3]. For example, it has been shown that diastolic heart failure may be as frequent as systolic heart failure and may have a long-term mortality rate that approaches that of systolic heart failure [4]. Moreover, the incidence of diastolic heart failure is increasing in the general population and is expected to become a major health care problem as the population of the United States ages [5].

Diastolic dysfunction with preservation of the LVEF can occur without the symptoms of heart failure, and studies have suggested that isolated diastolic dysfunction can be related to mortality [1].

Although diastolic dysfunction with or without symptoms of heart failure can occur with preserved LVEF, it has been speculated that systolic function may indeed not be normal [2].

The purpose of the present study was to determine if systolic function is normal in patients who have diastolic dysfunction and a preserved LVEF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 Acknowledgment
 References
 
2.1. Patients
Between February 3, 1987, and December 10, 1998, 1650 clinically requested resting radionuclide ventriculograms were performed at the Mayo Clinic Nuclear Cardiology Laboratory. Of these, 437 were performed to evaluate the cardiac effects of chemotherapeutic agents and were excluded from analysis in the present study. Another 110 studies were excluded because either the radionuclide raw data were not available for review (n=100) or were unsatisfactory for reanalysis (n=10). The study was limited to patients 45 years or older because the incidence of diastolic dysfunction is known to be increased in older persons. Thus, the 111 studies performed in patients younger than 45 years were excluded. An LVEF of 0.50 or greater was considered to indicate preserved LVEF; thus, the 504 studies in which the LVEF was less than 0.50 were excluded. Also, 49 repeat studies were excluded. After all these exclusions, radionuclide ventriculograms from 439 patients 45 years or older with a resting LVEF of 0.50 or greater were analyzed in the study. The Mayo Foundation Institutional Review Board approved the study. Consent to examine medical records was available for all patients, as per Minnesota Statute 144.335.

2.2. Clinical information
The following clinical information was recorded for each patient: age, sex, reason for radionuclide ventriculography being performed [chest pain diagnosis, assessment of coronary artery disease (CAD), or assessment of left ventricular (LV) function], major symptom before radionuclide ventriculography (atypical chest pain, typical angina, or dyspnea), the presence or absence of a history of cigarette use, the presence or absence of a family history of CAD, the presence or absence of a history of hypercholesterolemia, the presence or absence of diabetes mellitus, and the presence or absence of hypertension. In addition, the presence or absence of a history of a previous myocardial infarction, clinically significant valvular heart disease, documented cardiomyopathy, a permanent pacemaker, a previous angioplasty procedure, or coronary artery bypass surgery was tabulated. Also, the presence or absence of the long-term use of nitrates, β-blockers, calcium channel blockers, digitalis, diuretics, or angiotensin-converting enzyme inhibitors or other antihypertensive agents was identified.

2.3. Radionuclide ventriculography
Gated bloodpool radionuclide ventriculography was performed, and the LV activity-versus-time curve (Fig. 1) was generated and analyzed using methods previously validated in this laboratory [6–8]. Patients with significant cardiac rhythm irregularity, including atrial fibrillation, did not undergo radionuclide ventriculography. The activity-versus-time curves of all patients were reviewed for accuracy by the author and recalculated if an error had occurred during the initial processing. The activity-versus-time curve was used to determine three measures of systolic function and one of diastolic function (Fig. 1). The first measure of systolic function was LVEF (LV end-diastolic activity minus LV end-systolic activity divided by LV end-diastolic activity). The second measure was obtained from the systolic emptying phase of the activity-versus-time curve and was the maximum rate of emptying [i.e., the peak ejection rate (PER) calculated in LV end-diastolic volumes per second]. The third measure was LV end-systolic volume. With the use of a previously validated attenuation-uncorrected algorithm [6–8], LV end-systolic activity normalized to bloodpool activity was used to calculate LV end-systolic volume in milliliters. The single measure of LV diastolic function was determined from the diastolic phase of the LV activity-versus-time curve and was the maximum rate of filling in the initial rapid filling period [i.e., the peak filling rate (PFR) in LV end-diastolic volumes per second].


Figure 1
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  		Fig. 1 Representative LV volume-versus-time curve. The Y-axis indicates LV volume as a proportion of LV end-diastolic volume and is directly proportional to LV radionuclide count activity. The peak ejection point is indicated on the emptying portion of the curve; PER is the peak ejection rate at that point, measured in end-diastolic volumes per second. The peak filling point is indicated on the initial rapid filling portion of the curve; PFR is the peak filling rate at that point, measured in end-diastolic volumes per second. LV ejection fraction equals LV activity at end-diastole minus LV activity at end-systole divided by LV activity at end-diastole. LV end-systolic volume can be derived from radionuclide LV count activity at end-systole [6].

 
Previously published data were used to define normal and abnormal values for PER and PFR [9,10]. These studies included 60 subjects who were either patients or volunteers and had no risk factors for CAD and had normal LV wall motion and ejection fraction at rest and exercise. All the subjects were considered to have a low likelihood of cardiac pathology. Thirty-seven subjects were 45 years or older, and the 10th percentile value of PER for these 37 subjects was determined; this value was –2.66 LV end-diastolic volumes per second. For the present study, a PER less than –2.66 LV end-diastolic volumes per second was considered abnormally low and a PER of –2.66 or greater was considered normal. The normal value for LV PFR was defined as the value for PFR between and including the 10th percentile and 90th percentile values found in the 37 subjects. The 10th and 90th percentile values for PFR were 2.40 and 3.78 LV end-diastolic volumes per second, respectively. Values of PFR less than 2.40 or greater than 3.78 LV end-diastolic volumes per second were considered abnormally low and high, respectively.

In all study patients, heart rate (beats/min) and systolic and diastolic blood pressures (mm Hg) were measured at the time of radionuclide ventriculography. LV end-diastolic and end-systolic volumes (in milliliters) were calculated, as noted above.

LV wall motion was determined from the cine display of the radionuclide ventriculogram viewed in anterior, left lateral, and left anterior oblique projections by two experienced observers. LV wall motion was described as "normal" if all ventricular walls contracted vigorously, and "abnormal" if any region of the LV showed diminished contraction.

2.4. Statistics
Continuous variables were summarized as the mean and standard deviation (S.D.), and noncontinuous variables were summarized as percentages.

Comparisons between groups, for continuous variables, were performed using ANOVA, with a P value for the t statistic of ≤.05 being considered significant. Comparisons between noncontinuous variables were performed using the {chi}2 statistic. P≤0.05 of the {chi}2 statistic was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 Acknowledgment
 References
 
The demographic and clinical features are documented in Table 1. Just over half of the 439 patients were male, and the majority of patients (65%) had the radionuclide study for evaluation of chest pain or CAD. Chest discomfort was the major symptom in 30% of patients and dyspnea in 26%. Cardiac risk factors were common in this population: 51% had a history of smoking, 41% had hyperlipidemia, 56% had hypertension, 25% had a history of previous myocardial infarction, and 28% had had a revascularization procedure. Many patients were taking cardioactive medications (Table 2). The hemodynamic findings in the 439 patients are listed in Table 3. The mean LVEF in the 439 patients was 0.62±0.08. LV end-diastolic volume averaged 174±79 ml, and LV end-systolic volume averaged 71±38 ml. The mean PER was –3.22±0.74 LV end-diastolic volumes per second, and the mean PFR was 2.66±0.87 LV end-diastolic volumes per second. Ninety-eight (22%) patients had an abnormal PER, and 240 (55%) had either an abnormally low (193 patients, 44%) or abnormally high (47 patients, 11%) PFR. Abnormal LV wall motion occurred in 156 (36%) patients.


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  		Table 1 Demographic and clinical features of the study population (N=439)

 


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  		Table 2 Cardiac medications taken by the study population

 


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  		Table 3 Hemodynamic features of the study population

 
3.1. Systolic and diastolic function in relation to preserved LVEF
To relate systolic and diastolic function to the level of preserved LVEF, three subgroups were defined on the basis of the 33rd and 66th percentile values for LVEF, which were 0.58 and 0.64, respectively. Group 1, low-normal LVEF, consisted of 147 (33%) patients with LVEF ranging from 0.50 through 0.58 (mean±S.D., 0.53±0.02); group 2, intermediate-normal LVEF, consisted of 161 (37%) patients with LVEF ranging from 0.59 through 0.64 (0.61±0.02); and group 3, high-normal LVEF, consisted of 131 (30%) patients with LVEF ranging from 0.65 through 0.94 (0.72±0.06). Among the three LVEF groups, LV end-systolic volume was significantly (P<0.0001) different and decreased as LVEF increased from 93±36 ml in group 1, to 71±33 ml in group 2, and to 43±26 ml in group 3 (Fig. 2, left).


Figure 2
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  		Fig. 2 Left: Left ventricular end-systolic volume (LVESV), middle, peak ejection rate (PER), and right, peak filling rate (PFR) in patients with low-normal (white bars), intermediate-normal (gray bars), and high-normal (black bars) left ventricular ejection fractions. Significant differences exist among these three groups for LVESV, PER, and PFR. EDV=end-diastolic volume.

 
PER increased significantly (P<0.0001) from group 1 (–2.78±0.50) to group 2 (–3.13±0.47) to group 3 (–3.83±0.84) (Fig. 2, middle). It is of note that the proportion of patients with abnormal PER (Fig. 3A) decreased significantly (P<0.0001) from group 1 (69 patients, 47%) to group 2 (22 patients, 14%) to group 3 (7 patients, 5%).


Figure 3
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  		Fig. 3 (A) Frequency of normal (light gray sectors) and abnormal (dark gray sectors) PER when the LVEF was low-normal (left), intermediate-normal (middle), and high-normal (right). The differences among the three groups were significant (P<0.0001). (B) Frequency of abnormally low (dark gray sectors), normal (light gray sectors), and abnormally high (white sectors) PFR when the LVEF was low-normal (left), intermediate-normal (middle), and high-normal (right). The differences among the three groups were significant (P<0.0001).

 
Diastolic function as measured by PFR increased significantly (P<0.0001) from group 1 (2.31±0.74) to group 2 (2.58±0.74) to group 3 (3.15±0.94) (Fig. 2, right). In addition, the proportion of patients with abnormally low PFR decreased significantly (P<0.0001) from group 1 (93 patients, 63%) to group 2 (75 patients, 47%) to group 3 (25 patients, 19%) (Fig. 3B), and the proportion of patients with abnormally high PFR increased significantly (P<0.0001) from group 1 (5 patients, 3%) to group 2 (15 patients, 9%) to group 3 (27 patients, 21%) (Fig. 3B).

The proportion of patients with abnormal LV wall motion decreased significantly (P<0.0001) from group 1 (84, 57%) to group 2 (55, 34%) to group 3 (17, 13%).

3.2. Association of PER and PFR
Of the 439 study patients with preserved LVEF, 193 (44%) had an abnormally low PFR and, of these, 65 (34%) had an abnormally low PER (Fig. 4). One hundred ninety-nine patients (45%) with preserved LVEF had a normal PFR and, of these, 32 (16%) had an abnormally low PER. Only 47 patients in the study group (11%) had an abnormally high PFR and, of these 47, only 1 (2%) had an abnormally low PER. The pattern of PER between the PFR groups was significantly different (P<0.0001).


Figure 4
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  		Fig. 4 Frequency of normal (light gray sectors) and abnormally low (dark gray sectors) PER when the PFR was abnormally low (left), normal (middle), and abnormally high (right). The differences among the three groups were significant (P<0.0001). The number of patients in each PFR group is indicated beneath each panel.

 
3.3. Clinical differences among the three LVEF subgroups
The distribution of clinical findings and medications listed in Tables 1 and 2 were analyzed to determine if these differed among the LVEF groups (Table 4). Significantly (P=0.002) more men were in the low-normal LVEF group (66%) than in the intermediate-normal (57%) and high-normal (44%) LVEF groups. Age did not differ significantly among the three LVEF subgroups. A history of previous myocardial infarction was more likely (P=0.005) in the low-normal (35%) than in the intermediate-normal (21%) and high-normal (19%) LVEF groups. In addition, a history of revascularization was more frequent (P=0.03) in the low-normal (35%) than in the intermediate-normal (24%) and high-normal (23%) LVEF groups. Atypical angina was significantly (P=0.001) more common in the high-normal (27%) than in the intermediate-normal (16%) and low-normal (10%) LVEF groups. A history of hypertension was more common (P=0.02) in the high-normal (61%) and intermediate-normal (61%) LVEF groups than in the low-normal (47%) LVEF group. The distribution of the other clinical measures and medications used did not differ among the three LVEF groups.


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  		Table 4 Demographic and clinical features and cardiac medications by LVEF group

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 Acknowledgment
 References
 
4.1. Main findings
The main finding of this study was that measures of both systolic and diastolic function were often abnormal in patients with a preserved LVEF. In patients with a low-normal LVEF (LVEF, 0.50–0.58), PFR was either abnormally low or high in 66%. LV end-systolic volume was high in this population, and almost one-half of the patients had an abnormally low PER. In patients with an intermediate-normal LVEF (LVEF, 0.59–0.64), PFR was abnormally low or high in almost half (56%) and PER was abnormally low in 14%. Even in the highest LVEF group (LVEF, 0.64–0.94), PFR was either abnormally high or low in 40% and PER was abnormally low in 5%. It is of note that in this population with preserved LVEF, one-half of the patients had an abnormally high or low PFR and, of these, one-third had an abnormal PER. Thus, in this population of patients with preserved LVEF, systolic and diastolic function were often abnormal.

4.2. Comparison with other studies
This study is the first to assess the frequency of systolic and diastolic dysfunction in an unselected referral patient population with preserved LVEF, using radionuclide ventriculography. With tissue Doppler imaging, Yu et al. [2] identified systolic dysfunction in 52% of patients with diastolic heart failure and 14% of those with diastolic dysfunction without symptomatic heart failure. The patients with isolated diastolic dysfunction in the study of Yu et al. had a high incidence of ischemic heart disease that was similar to the frequency of CAD in the present study. The present study and that of Yu et al. support the concept of combined systolic and diastolic dysfunction in the presence of relatively well-preserved LVEF, as enunciated by Zile and Brutsaert [11].

Consistent with the hypothesis of Zile and Brutsaert [11], patients with low-normal LVEF had the greatest incidence of reduced PFR and almost half of them had an abnormally low PER. It is also of note that the hypothesis of Zile and Brutsaert suggested that combined systolic and diastolic dysfunction with a relatively well-preserved LVEF also was associated with a modestly increased LV end-systolic volume. The present study found that LV end-systolic volume was indeed increased in patients with low-normal LVEF and abnormal PFR and abnormal PER, adding support to the hypothesis of Zile and Brutsaert.

Thus, the present study provides evidence that diastolic dysfunction in the presence of preserved LVEF is often accompanied by abnormal systolic function.

It is remarkable that 55% of patients in the present study had abnormal diastolic filling. The incidence of heart failure in the study population was not determined. The frequency of diastolic filling abnormality in patients with cardiovascular pathology and preserved LVEF without heart failure symptoms has yet to be determined. Redfield et al. [1] found a 29% incidence of abnormal filling abnormalities in a randomly selected population with preserved LVEF in Olmsted County, MN, using Doppler echocardiography; only 1–2% of these patients had a history of congestive heart failure. Cardiac risk factors and lesions were quite prevalent in this community population (59% had a smoking history, 4.5% had diabetes mellitus, 28% had hypertension, and 17% had CAD) but less so than in the referral population of the present study. The findings of Redfield et al. suggest that the high incidence of diastolic abnormality identified in the referral population analyzed in the present study would not be unexpected.

One-third of the patients in this study had abnormal wall motion, reflecting the moderate frequency of overt CAD in this population. Abnormal wall motion was most common in the subgroup with low-normal LVEF (57% of patients). Of the LVEF subgroups, the latter subgroup also had the greatest incidence of overt CAD. These findings are consistent with the clinical experience that CAD is a common cause of diastolic dysfunction.

4.3. Study limitations
A major limitation of the study was that it was not performed solely in patients with heart failure and preserved LVEF, nor was it performed purely in patients with asymptomatic diastolic dysfunction. Also, the study was not a randomized investigation but an observational study of consecutive patients referred to a tertiary referral center. Consequently, many of the patients had a cardiac abnormality. In the study population, no attempt was made to identify patients with a history of heart failure at the time of radionuclide ventriculography. From 26% of patients, a history of dyspnea was elicited prospectively and was the major reason for assessing ventricular function. The incidence of dyspnea did not differ among the LVEF groups. Another limitation of the study was that signs of heart failure were not recorded at the time of radionuclide ventriculography. It is suspected that the frequency of signs of heart failure at the time of radionuclide ventriculography may be low in the study population because a separate analysis of the last 100 patients enrolled in the study was performed. In these 100 patients, the referring physician's examination was inspected for identification of signs of heart failure. Two patients had an elevated jugular venous pressure, 4 had pulmonary rales, and 16 had ankle edema. No patient had all three signs of heart failure, and only three had two of the three signs. Thus, the findings of this study are not applicable to patients with heart failure and preserved systolic function. Nor are the findings applicable to patients with asymptomatic diastolic dysfunction because 26% of them admitted to dyspnea. The study provides information relevant to patients with preserved LVEF who were referred to a tertiary cardiac center for evaluation. The study results do suggest that patients with diastolic heart failure should have a more detailed assessment of LV systolic function because a preserved LVEF does not necessarily mean preserved LV function.

Many of the patients in the present study were taking cardiac medications, some of which are known to influence diastolic function (diuretics, digoxin, β-blockers, and calcium channel blockers). These agents possibly altered the frequency of diastolic and systolic abnormalities in this patient population.

Variations in LV hypertrophy in the study population could account for the observed variations in LV emptying and filling observed in the population. A subsequent review of the last 100 patients enrolled in the study revealed that out of 96 patients who had a 12-lead electrocardiogram concurrent with radionuclide ventriculography, nine had standard electrocardiographic criteria of LV hypertrophy. To assess more critically the role of LV hypertrophy in determining variations in LV emptying and filling, a more detailed quantification of LV hypertrophy would be required.

Because of the ready availability, echocardiography and Doppler echocardiography are often used to assess systolic and diastolic function noninvasively. Radionuclide ventriculography may be considered superior to echocardiography for measurement of LVEF because of its nongeometric basis and excellent reproducibility [12]. The method used for radionuclide measurement of cardiac volumes was an attenuation-uncorrected method and, thus, may be in error when body habitus causes relatively less or more tissue attenuation [13].

The LV radionuclide activity-versus-time curve is a well-validated method for noninvasively determining the rate of volume changes in the LV with PER used as a measure of systolic function [14–16] and PFR established as a measure of diastolic function [17–19]. Doppler echocardiography has shown that the mitral valve inflow pattern may be normal when left atrial pressure is increased [20]. In this circumstance, mitral valve inflow is termed "pseudonormal." Radionuclide ventriculography cannot distinguish between patients with pseudonormal diastolic filling and those with normal filling. The number of patients with pseudonormal filling in the present study is unknown. However, the definition of abnormal filling in the present study was based on the extremes of PFR in a normal population, and, therefore, it can reasonably be presumed that diastolic filling is indeed abnormal in these circumstances. Because the radionuclide method cannot identify pseudonormal filling, the present study likely underestimated the frequency of abnormal filling in the study population.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
Acknowledgment
 References
 
Systolic function was abnormal in patients with preserved LVEF. Diastolic and systolic dysfunction were often combined in the presence of preserved LVEF.


   Acknowledgment
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgment
References
 
The author thanks the Cardiovascular Research Studies Unit for excellent work in abstracting data.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgment
 References
 

  1. Redfield M.M., Jacobsen S.J., Burnett J.C. Jr., Mahoney D.W., Bailey K.R., Rodeheffer R.J. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA (2003) 289:194–202.[Abstract/Free Full Text]
  2. Yu C.M., Lin H., Yang H., Kong S.L., Zhang Q., Lee S.W. Progression of systolic abnormalities in patients with "isolated" diastolic heart failure and diastolic dysfunction. Circulation (2002) 105:1195–1201.[Abstract/Free Full Text]
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  10. Clements I.P., Bailey K.R., Zachariah P.K. Effects of exercise and therapy on ventricular emptying and filling in mildly hypertensive patients. Am. J. Hypertens. (1994) 7:695–702.[Web of Science][Medline]
  11. Zile M.R., Brutsaert D.L. New concepts in diastolic dysfunction and diastolic heart failure: Part I. Diagnosis, prognosis, and measurements of diastolic function. Circulation (2002) 105:1387–1393.[Free Full Text]
  12. van Royen N., Jaffe C.C., Krumholz H.M., et al. Comparison and reproducibility of visual echocardiographic and quantitative radionuclide left ventricular ejection fractions. Am. J. Cardiol. (1996) 77:843–850.[CrossRef][Web of Science][Medline]
  13. Zaret B.L., Wackers F.J. Nuclear cardiology—second of two parts. N. Engl. J. Med. (1993) 329:855–863.[Free Full Text]
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  15. Marcassa C., Galli M., Campini R., Marzullo P., Giannuzzi P. Differential systolic and diastolic effects of β-adrenergic stimulation in patients with severe left ventricular dysfunction: a radionuclide ventriculographic study. J. Nucl. Cardiol. (2003) 10:46–50.[CrossRef][Web of Science][Medline]
  16. Cuocolo A., Nicolai E., Fazio S., et al. Impaired left ventricular diastolic filling in patients with acromegaly: assessment with radionuclide angiography. J. Nucl. Med. (1995) 36:196–201.[Abstract/Free Full Text]
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