Download Left Ventricular Diastolic Function in Patients With

Left Ventricular Diastolic Function in
Patients With Advanced Cystic Fibrosis*
Todd M. Koelling, MD; G. William Dec, MD; Leo C. Ginns, MD, FCCP; and
Marc J. Semigran, MD
Objectives: To assess left ventricular systolic and diastolic function in adult patients with cystic fibrosis
using radionuclide ventriculography.
Background: Although myocardial fibrosis has been described in autopsy specimens of patients with
cystic fibrosis, the possibility that myocardial dysfunction may occur during life in adult patients with
cystic fibrosis has not been explored.
Methods: To assess the possibility of cardiac dysfunction occurring in cystic fibrosis, we studied
40 patients with advanced cystic fibrosis with first-pass radionuclide ventriculography and compared
them to 9 patients with advanced bronchiectasis and 18 normal control subjects.
Results: Indexes of right ventricular systolic function were similarly impaired in patients with cystic
fibrosis and patients with bronchiectasis. Left ventricular ejection fraction of patients with cystic
fibrosis, patients with bronchiectasis, and normal control subjects did not differ. Fractional left
ventricular filling at 50% of diastole, an index of diastolic function, was significantly lower in patients
with cystic fibrosis (54 ⴞ 13%, mean ⴞ SD) in comparison to patients with bronchiectasis (66 ⴞ 4%,
p ⴝ 0.009) or normal control subjects (69 ⴞ 14, p ⴝ 0.0002). The contribution of atrial systole to total
diastolic left ventricular filling was greater in patients with cystic fibrosis (38 ⴞ 18%) than in patients
with bronchiectasis (21 ⴞ 4%, p ⴝ 0.01) or normal control subjects (25 ⴞ 12%, p ⴝ 0.01).
Conclusions: Patients with advanced cystic fibrosis demonstrate impaired left ventricular distensibility when compared to normal control subjects and patients with bronchiectasis. Patients with cystic
fibrosis may be at risk of heart failure due to right ventricular dysfunction or left ventricular diastolic
dysfunction.
(CHEST 2003; 123:1488 –1494)
Key words: cystic fibrosis; diastolic dysfunction; radionuclide ventriculography
Abbreviations: BSA ⫽ body surface area; LVEDV ⫽ left ventricular end-diastolic volume; LVEF ⫽ left ventricular ejection
fraction; RVEF ⫽ right ventricular ejection fraction; V̇o2 ⫽ oxygen consumption
fibrosis is a systemic disease characterized
C byysticprogressive
deterioration of organ function
and the development of scarring and fibrosis. In the
past 20 years, several case reports have described
children with cystic fibrosis dying with signs and/or
symptoms of left ventricular dysfunction who were
later found to have myocardial fibrosis at autopsy.1,2
Despite this, left ventricular function has not been
systematically investigated in patients with cystic
fibrosis, although the effects of cystic fibrosis on the
*From the Heart Failure and Cardiac Transplantation Center,
Cardiology Division, (Drs. Koelling, Dec, and Semigran), and the
Pulmonary Unit (Dr. Ginns), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Manuscript received October 19, 2001; revision accepted November 8, 2002.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
Correspondence to: Marc J. Semigran, MD, MGH Heart Failure
and Cardiac Transplantation Center, Massachusetts General
Hospital, Bigelow 645, 55 Fruit St, Boston, MA 02114; e-mail:
[email protected]
right ventricle have been well described by previous
investigators, and include abnormalities of structure
and systolic function.3– 8
As the longevity of patients with cystic fibrosis is
extended with the use of newer antibiotics, lung
transplantation, and the possibility of successful gene
therapy, a process of progressive fibrosis of myocardium may have functional significance and could
lead to the development of heart failure in these
patients. In order to determine if patients with cystic
fibrosis, without symptomatic heart failure, would
exhibit impairment of myocardial function, we compared indexes of systolic and diastolic function in
these patients with a group of patients with bronchiectasis who did not have abnormal epithelial chloride
conductance, and with a control population.
Materials and Methods
Patient Population
The study population was composed of 49 patients and 18
normal volunteers who served as control subjects. The patients
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Clinical Investigations
were classified into two groups: 40 patients with advanced cystic
fibrosis, and 9 patients with advanced bronchiectasis in whom
diagnostic testing results for cystic fibrosis were negative. All
patients had been referred to the Massachusetts General Hospital for consideration of lung transplantation. Data compiled for
each patient or control subject included clinical history and
physical examination, and the results of routine echocardiography
with Doppler examination, exercise testing, radionuclide ventriculography, and spirometry. The frequency of prescription of
supplemental oxygen by the patient’s physician was assessed.
Correlations of demographic data, physical examination findings,
pulmonary function data, with radionuclide ventriculography
measurements were performed using the Spearman rankcorrelation method for nonparametric data. Data are presented
as mean ⫾ SD. For all analyses, a two-tailed p value ⬍ 0.05 was
considered statistically significant.
Results
Study Population
Cardiopulmonary Exercise Testing
Cardiopulmonary exercise testing was performed by previously
reported methods.9 In brief, upright bicycle ergometry (pedal
ergometer; Warren E. Collins; Braintree, MA) was used with a
12.5 W/min or 25 W/min incremental ramp protocol based on
predicted exercise capacity, and was performed following an
overnight fast with all patients breathing air. Breath-by-breath
expired gas analysis was performed by a metabolic cart (Beckman
OM1; Beckman Instruments; Fullerton, CA) interfaced to the
ergometer. Peak oxygen uptake was defined as the highest oxygen
consumption (V̇o2) measured during the last minute of symptomlimited exercise. The anaerobic threshold was determined by the
V-slope method.10 Exercise testing was delayed if patients required a course of antibiotics until their pulmonary infection had
improved.
First-Pass Radionuclide Ventriculography
Rest and exercise first-pass radionuclide ventriculography was
performed at the time of bicycle ergometry. Patients were seated
upright on the cycle ergometer facing a multicrystal nuclear
camera (System 77; Baird Corporation; Bedford, MA). Images
were acquired at 0.025-s intervals after central venous bolus
administration of autologous erythrocytes labeled with 10 mCi
99m
Tc at rest and with 15 mCi at peak exercise. Left and right
ventricular regions of interest were chosen based on maximum
intensity of radioactive counts as depicted by color and identification of valvular planes. Time-activity curves were generated for
each region of interest by imaging software (SIM-400; Scinticor;
Milwaukee, WI). Only cycles with ⬎ 70% of the maximal enddiastolic activity in the end-diastolic frame were included in the
analysis. Lung background counts were subtracted from the
time-activity curves representing each cardiac cycle. The background curves were then summed to create a single representative cardiac cycle. Peak activity was considered to be end-diastole
and minimum activity was considered to be end-systole.
The ejection fraction of each ventricle was calculated as (enddiastolic counts ⫺ end-systolic counts)/end-diastolic counts. The left
ventricular end-diastolic volume (LVEDV) was determined using a
previously described geometric area-length method.11 Atrial filling
contribution, time to peak filling rate, and filling at 50% of diastole
were determined from the time-activity curves.12 The period of
atrial contraction was taken to begin 40 ms prior to the beginning of
the PR interval of a 12-lead ECG (thereby compensating for
electromechanical delay) and terminate at end-diastole. Peak filling
rate and filling at 50% of diastole were determined from the diastolic
portion of the time-activity curve.
Statistical Analysis
Rates and proportions were compared using ␹2 tests of general
association or Fisher exact tests where appropriate. The unpaired
Student t test with assumption of equal variance was used to
compare the means of normally distributed continuous variables.
The clinical characteristics of the study populations are shown in Table 1. The mean age of patients
with cystic fibrosis was similar to the bronchiectasis
population and less than the control subjects. Patients with cystic fibrosis were smaller than the
comparison populations, as assessed by body surface
area (BSA). None of the patients with cystic fibrosis
were known to have prior cardiac disease, nor were
they receiving any cardiac medications. The arterial
oxygen tension in the cystic fibrosis populations and
the patients with bronchiectasis were similar, measured prior to exercise breathing air. However, supplemental oxygen was prescribed more frequently
for patients with cystic fibrosis (2 L/min, n ⫽ 11;
3 L/min, n ⫽ 6; 4 L/min, n ⫽ 3; 5 L/min, n ⫽ 1) than
for patients with bronchiectasis (3 L/min, n ⫽ 1)
[Table 1]. Spirometry revealed that the patients with
cystic fibrosis had more severe lung disease, with a
lower vital capacity and FEV1 than the patients with
bronchiectasis. The oxygen saturations and pulmonary function test results of the control subjects were
verified to be normal.
Echocardiography
Echocardiography was technically satisfactory for
analysis of the right ventricle in 34 of the 40 patients
with cystic fibrosis and 8 of the 9 patients with
bronchiectasis (Table 2). Left ventricular and left
Table 1—Clinical Characteristics*
Characteristics
Cystic
Fibrosis
(n ⫽ 40)
Bronchiectasis
(n ⫽ 9)
Age, yr
Female gender, %
BSA, m2
Supplemental O2, %
% predicted FEV1, %
% predicted FVC, %
Dlco, mm/min/mm Hg
29 ⫾ 8†
44
1.5 ⫾ 0.2†‡
52†
23 ⫾ 8†
39 ⫾ 12‡
15 ⫾ 5
33 ⫾ 7
44
1.8 ⫾ 0.3
11
45 ⫾ 38
61 ⫾ 28
14 ⫾ 5
Normal
Control
(n ⫽ 18)
37 ⫾ 12
50
1.8 ⫾ 0.2
*Data are presented as mean ⫾ SD; supplemental O2 ⫽ percentage
of patients receiving O2; Dlco ⫽ diffusing capacity of the lung for
carbon monoxide.
†p ⬍ 0.01 vs normal control.
‡p ⬍ 0.01 vs bronchiectasis.
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1489
Table 2—Echocardiography Data*
Cystic
Fibrosis
(n ⫽ 34)
Bronchiectasis
(n ⫽ 8)
29 ⫾ 3
19 ⫾ 3
5.7 ⫾ 0.7†
65 ⫾ 8
44
12
29
15
26 ⫾ 5
18 ⫾ 2
5.1 ⫾ 0.7
70 ⫾ 9
38
0
12
14
Variables
LVIDD, mm/m2
Left atrium, mm/m2
Interventricular septum, mm/m2
LVEF
Right ventricle dilation
Right ventricle hypokinesis
Septal flattening
Tricuspid regurgitation, milder
or greater
*Data are presented as mean ⫾ SD or %. LVIDD ⫽ left ventricular
internal diastolic dimension.
†p ⬍ 0.05 vs bronchiectasis.
atrial size, indexed to BSA, were no different between patients with cystic fibrosis and patients with
bronchiectasis. The interventricular septal thickness
of patients with cystic fibrosis (5.7 ⫾ 0.7 mm/m2)
was significantly larger than patients with bronchiectasis (5.1 ⫾ 0.7 mm/m2, p ⬍ 0.05). Left ventricular
ejection fraction (LVEF) was normal and similar in
the two groups of patients. The presence of right
ventricular dilation or hypokinesis was noted in a
minority of patients and with similar frequency in the
two groups of patients. Flattening of the interventricular septum during systole suggesting right ventricular pressure overload was also observed with
similar frequency in the two groups, as was the
presence of significant tricuspid regurgitation (mild
or greater, by color Doppler echocardiography).
Doppler echocardiographic measurement of the velocity of the tricuspid regurgitation jet revealed
severe elevation of the estimated right ventricular
systolic pressure (⬎ 50 mm Hg) in two patients with
cystic fibrosis. Because only a small percentage of
patients had tricuspid regurgitation, the estimated
right ventricular systolic pressures of the two groups
of patients were not compared. No other echocardiographic abnormalities were noted.
Cardiopulmonary Exercise Testing
The results of cardiopulmonary exercise testing in
the study population are shown in Table 3. All
patients exercised while breathing room air. The
patients with cystic fibrosis had similar exercise
tolerance to the patients with bronchiectasis, with
both patient groups having less exercise capacity
than control subjects as measured by peak workload,
peak V̇o2, and V̇o2 at the anaerobic threshold. Each
of the patients with cystic fibrosis and patients with
bronchiectasis reached a pulmonary limit to exercise.
Peak workload achieved by patients with cystic fibrosis was less than observed in patients with bronchiectasis, but no difference was seen with respect to
peak V̇o2 or V̇o2 at the anaerobic threshold. The
resting heart rate of the patients with cystic fibrosis
was higher than either the patients with bronchiectasis (87 ⫾ 23 beats/min) or the normal control
subjects (82 ⫾ 13 beats/min), although the heart rate
at peak exercise did not differ. The mean systemic
BP at rest was similar in all three groups; however,
the systemic BP achieved at peak exercise was lower
in the patients with cystic fibrosis than the patients
with bronchiectasis. The Pao2 of the patients with
cystic fibrosis and patients with bronchiectasis was
similar at rest and at peak exercise.
Radionuclide Ventriculography
Right and left ventricular systolic function was
assessed by radionuclide ventriculography performed at rest and peak exercise (Table 4). The rest
and exercise right ventricular ejection fractions
Table 3—Exercise Data*
Variables
Cystic Fibrosis
(n ⫽ 40)
Bronchiectasis
(n ⫽ 9)
Normal Control
(n ⫽ 18)
Peak work, W
Peak V̇o2, mL/min/kg
V̇o2 anaerobic threshold, mL/min/kg
Mean BP, at rest, mm Hg
Mean BP, at peak exercise, mm Hg
Heart rate at rest, beats/min
Heart rate at peak exercise, beats/min
Pao2 at rest, mm Hg
Pao2 at exercise, mm Hg
Paco2 at rest, mm Hg
46 ⫾ 24†‡
16.7 ⫾ 5.8†
10.2 ⫾ 3.1†
79 ⫾ 17
108 ⫾ 17‡
107 ⫾ 19†‡
148 ⫾ 16
68 ⫾ 11
64 ⫾ 11
42 ⫾ 7
75 ⫾ 38†
15.8 ⫾ 5.9†
10.4 ⫾ 4.1†
88 ⫾ 7
120 ⫾ 14†
87 ⫾ 23
135 ⫾ 27
68 ⫾ 8
61 ⫾ 13
41 ⫾ 8
132 ⫾ 45
24.5 ⫾ 5.3
17.1 ⫾ 4.5
84 ⫾ 17
103 ⫾ 18
82 ⫾ 13
159 ⫾ 16
*Data are presented as mean ⫾ SD.
†p ⬍ 0.001 vs normal control.
‡p ⬍ 0.001 vs bronchiectasis.
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Clinical Investigations
Table 4 —Radionuclide Ventricular Systolic
Function Data*
Variables
RVEF at rest
RVEF at exercise
LVEF at rest
LVEF at exercise
LVEDVI at rest,
mL/m2
LVEDVI at exercise,
mL/m2
Cystic
Fibrosis
(n ⫽ 40)
Bronchiectasis
(n ⫽ 9)
Normal
Control
(n ⫽ 18)
0.34 ⫾ 0.07†
0.35 ⫾ 0.07†
0.62 ⫾ 0.08
0.64 ⫾ 0.11
81 ⫾ 15‡
0.36 ⫾ 0.07†
0.39 ⫾ 0.07†
0.61 ⫾ 0.08
0.70 ⫾ 0.12
77 ⫾ 18‡
0.44 ⫾ 0.08
0.47 ⫾ 0.08
0.62 ⫾ 0.06
0.66 ⫾ 0.08
65 ⫾ 10
91 ⫾ 19‡
82 ⫾ 12
76 ⫾ 10
*Data are presented as mean ⫾ SD; LVEDVI ⫽ LVEDV/BSA.
†p ⬍ 0.05 vs normal control.
‡p ⬍ 0.01 vs normal control.
(RVEFs) were lower in the patients with cystic
fibrosis and the patients with bronchiectasis when
compared with the normal control subjects, and did
not differ between the two patient populations. The
observed decrease in rest and exercise RVEF persisted after the two cystic fibrosis patients with
echocardiographic right ventricular systolic pressure
⬎ 50 mm Hg were excluded from analysis. Left
ventricular dilation was also present in the patients
with cystic fibrosis, as LVEDV indexed to BSA, at
both rest and exercise, was 25% greater than in the
control population.
The results of assessment of left ventricular diastolic function at rest by radionuclide ventriculography are shown in Table 5. Fractional left ventricular
filling at mid-diastole was lower in the patients with
cystic fibrosis than either the patients with bronchiectasis or normal control subjects, and the contribution of atrial contraction to left ventricular filling was
higher. Neither peak left ventricular filling rate nor
time to left ventricular peak filling indexed to the
R-R interval differed in the study populations. These
observations are consistent with a restrictive pattern
of ventricular filling.
Clinical Correlates of the Results of Radionuclide
Ventriculography
Correlation of radionuclide indexes of right and
left ventricular systolic and diastolic function with
demographic data, physical examination findings,
and pulmonary function data were performed using
nonparametric techniques. RVEF at rest was found
to correlate with FEV1 (r ⫽ 0.37, p ⫽ 0.03). Both
fractional left ventricular filling at 50% of diastole
and atrial contribution to filling were found to
correlate with resting heart rate (r ⫽ ⫺ 0.54,
p ⬍ 0.001, and r ⫽ 0.60, p ⬍ 0.001, respectively)
and female gender (r ⫽ ⫺0.51, p ⬍ 0.001, and
r ⫽ 0.36, p ⫽ 0.02, respectively). There was no significant correlation between fractional left ventricular filling at 50% of diastole or atrial contribution to
filling and supplemental oxygen use, Pao2 at rest or
exercise, right ventricular dilation, right ventricular
hypokinesis, or septal flattening by echocardiography, or RVEF at rest or exercise by radionuclide
ventriculography. When patients with evidence of
septal flattening by echocardiography were excluded
from the analysis, the remaining patients with cystic
fibrosis (n ⫽ 25) continued to show lower fractional
filling at 50% of diastole (0.54 ⫾ 0.12) and higher
atrial filling contributions (0.38 ⫾ 0.18) than patients
with bronchiectasis (n ⫽ 8, 0.66 ⫾ 0.04 and
0.21 ⫾ 0.04, respectively; p ⫽ 0.01 for each).
Discussion
This study shows that adult patients with advanced
lung disease from cystic fibrosis demonstrate impairment of cardiac function when compared to patients
with bronchiectasis and normal control subjects.
While left ventricular systolic function was normal in
both groups of patients, patients with cystic fibrosis
had impaired left ventricular diastolic filling and
were more reliant on the atrial contribution to filling
when compared to patients with bronchiectasis or
normal control subjects. We also observed that right
Table 5—Radionuclide Ventricular Diastolic Function Data*
Variables
Cystic Fibrosis
(n ⫽ 40)
Bronchiectasis
(n ⫽ 9)
Normal Control
(n ⫽ 18)
Left ventricular filling at 50% of diastole
Atrial filling contribution
Left ventricular peak filling rate, end-diastolic volume/s
Time to left ventricular peak filling rate/R-R interval
0.54 ⫾ 0.13†
0.38 ⫾ 0.18‡§
3.8 ⫾ 1.1
0.25 ⫾ 0.07
0.66 ⫾ 0.04
0.21 ⫾ 0.08
3.5 ⫾ 0.9
0.21 ⫾ 0.08
0.69 ⫾ 0.14
0.25 ⫾ 0.12
3.4 ⫾ 0.9
0.22 ⫾ 0.06
*Data are presented as mean ⫾ SD.
†p ⬍ 0.01 vs bronchiectasis patients and normal control subjects.
‡p ⬍ 0.05 vs normal control.
§p ⬍ 0.001 vs bronchiectasis.
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ventricular systolic function both at rest and peak
exercise was similarly compromised in patients with
cystic fibrosis and patients with bronchiectasis. The
abnormal diastolic indexes in patients with cystic
fibrosis were found to be independent of arterial
oxygen tension, echocardiographic assessment of
right ventricular dilation or hypokinesis or interventricular septal flattening, or RVEF measured by
radionuclide ventriculography. When patients with
evidence of right ventricular pressure or volume
overload assessed by echocardiography were excluded from the analysis, the abnormalities of diastolic function in the patients with cystic fibrosis
persisted compared with normal control subjects or
patients with bronchiectasis. These abnormalities of
diastolic function are similar to those observed with
a restrictive cardiomyopathy.13
Ventricular Dysfunction in Patients With Cystic
Fibrosis
Although right ventricular dysfunction in patients
with cystic fibrosis has been described by previous
investigators,3– 6,14 left ventricular function has not
been studied extensively. Tomlin et al15 described
chronic cor pulmonale as a complication of fibrocystic disease of the pancreas in 1952. Allen et al,16
using echocardiography, identified increased right
ventricular wall thickness and cavity size in 37 children with cystic fibrosis, observing that these abnormalities occurred in patients with mild as well as
severe disease. Ryland and Reid17 identified right
ventricular hypertrophy at postmortem examination
in 83% of 36 patients with cystic fibrosis ⬎ 3 years old.
Our study expands on these observations, as we
observed that abnormalities in right ventricular systolic function are present at rest and persist to peak
exercise in patients with cystic fibrosis. Although
25% of the patients had RVEFs ⬍ 0.30, it is important to note that no patients with cystic fibrosis in the
population had more than mild (1⫹/4) pedal edema,
and only 8% had evidence of jugular venous distention. Only 2 of the 40 patients with cystic fibrosis
required therapy with diuretic medications. None of
the patients in this pretransplant population was
recommended to have combined heart-lung transplantation. One potential cause of right ventricular
systolic dysfunction may be an increase in afterload
related to destruction of pulmonary parenchyma. In
support of this, we found a correlation between
FEV1 and RVEF. We did not find a correlation
between RVEF and pulmonary arterial systolic pressure estimated from the velocity of the tricuspid
regurgitant jet; however, pulmonary arterial systolic
pressure may not be an accurate measure of after-
load in the presence of right ventricular dilation such
as was observed in the patient population.
The etiology of the observed left ventricular diastolic dysfunction in patients with cystic fibrosis is
potentially multifold. Right ventricular dilation may
decrease left ventricular distensibility through the
interventricular septum.18 The echocardiographic
observation of septal flattening in some of the patients with cystic fibrosis supports this mechanism;
however we did not observe an association of the
presence of septal flattening with impaired indexes
of ventricular filling. Other determinants of ventricular distensibility, such as tachycardia and increased
levels of neurohormonal mediators, may have had a
greater impact on ventricular filling and obscured
the effect of the right ventricular pressure and
volume overload on left ventricular function.
Studies of left ventricular function in patients with
cystic fibrosis have given clues that the disease may
be associated with a pathologic process that directly
effects the myocardium. Several case reports have
described children with cystic fibrosis with signs
and/or symptoms of left ventricular dysfunction who
were later found to have myocardial fibrosis at
autopsy.1,2
Allen et al16 showed that patients with cystic
fibrosis and severe pulmonary disease had thickened
septa, posterior walls, and aortas compared with
normal subjects by two-dimensional echocardiography. Our study confirms that the interventricular
septa of patients with cystic fibrosis are thickened as
compared to the patients with bronchiectasis. Benson et al19 studied 31 patients with cystic fibrosis
with exercise radionuclide ventriculography and
found that only 2 patients had LVEF ⬍ 55% at rest,
but 29% had impaired cardiac performance with
exercise. More recently, Herout et al20 described
skeletal and cardiac muscle pathologic changes in 26
children with cardiomyopathy and cystic fibrosis, 24
of whom subsequently died. Ambrosi et al21 studied
67 infants and children with cystic fibrosis and found
that 17 patients had LVEFs ⬍ 0.45, and 35% of
these had perfusion defects by scintigraphy compared to 8% of the patients with LVEFs ⬎ 0.45.
They surmised that these abnormalities were due to
myocardial fibrosis.
A more likely clinical manifestation of myocardial
fibrosis would be the development of impaired left
ventricular diastolic relaxation. Johnson et al22 studied 25 patients with cystic fibrosis using Doppler
echocardiography, examining left ventricular filling
patterns, and found that the proportion of atrial
filling was higher in these patients compared to
control subjects, and correlated with worsening pulmonary disease. Although the Doppler signal from
atrial filling is inversely associated with left ventric-
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Clinical Investigations
ular relaxation, transmitral flow velocities have been
shown to be closely related to both atrial filling
pressure and left ventricular diastolic pressure.23 For
this reason, we chose to assess the patients with
cystic fibrosis with radionuclide ventriculography to
assess left ventricular volumetric changes during
diastole.
Causes of myocardial fibrosis in patients with
cystic fibrosis are unknown. Zimmerman et al24
reported on pathology findings in two patients dying
of cystic fibrosis-associated cardiomyopathy in whom
myocardial edema was found and lymph stasis was
seen, suggesting that cystic fibrosis may be complicated by a disorder of cardiac lymphatic drainage.
Others have hypothesized that the fibrosis seen on
pathology samples occurs because of malnourishment and/or hypovitaminosis.2 Levels of neurohormonal mediators such as aldosterone and angiotensin
II are increased in patients with cystic fibrosis, and
these signaling molecules have previously been
shown to cause myocyte hypertrophy and interstitial
fibrosis.25,26 Certainly, chronic hypoxia can lead to
myocardial fibrosis,27 and this may have occurred in
the patients with cystic fibrosis we studied, as indicated by the need for supplemental oxygen in many
of them. Finally, the fundamental abnormality of
cystic fibrosis lies in chloride transport in epithelial
cells. Whether this abnormality alters either myocyte
calcium handling or myocardial collagen production
is unknown.
The implications of the finding of diastolic dysfunction in this population are twofold. First, advances in medical therapy for patients with cystic
fibrosis may lead to a population of patients in whom
dyspnea may have both pulmonary and cardiac contributions. Secondly, patients who have successful
lung transplantation and long-term survival from
improved allograft preservation may eventually acquire symptomatic left heart failure from progressive
left ventricular noncompliance. The study of ventricular function in cystic fibrosis patients after transplantation is warranted.
The indexes of diastolic function used in this study
were derived from changes in chamber volume over
time measured by radionuclide ventriculography.
These indexes have been shown previously to be
dependent on loading conditions, ejection fraction,
and heart rate.28 –31 We found no significant differences among the groups with respect to BP or LVEF
at rest. Patients with cystic fibrosis did have higher
resting heart rates, on average, than control subjects
or patients with bronchiectasis. Previous investigators have shown that higher heart rate increases the
peak ventricular filling rate, increases the early diastolic filling contribution, and decreases the atrial
filling contribution; however, despite the tendency of
a higher heart rate to improve diastolic relaxation,
the patients with cystic fibrosis were observed to
have impaired diastolic filling parameters. Future
assessment of diastolic function independent of loading conditions and heart rate may require the patients and controls to undergo micromanometer
left-heart and right-heart catheterization simultaneous with radionuclide ventriculography and right
atrial pacing.
We chose to compare indexes of myocardial systolic and diastolic function in patients with cystic
fibrosis with a group of patients with bronchiectasis
who did not have abnormal epithelial chloride conductance but in whom the pulmonary pathology is
similar to that of cystic fibrosis. The patients with
cystic fibrosis did have a greater degree of impairment of pulmonary function than the patients with
bronchiectasis, and we cannot completely exclude
the possibility that this contributed to the left ventricular diastolic dysfunction observed in the patients
with cystic fibrosis; however, the differences in
pulmonary function did not cause resting right and
left ventricular loading conditions to differ, given the
limitation imposed by the sample size to determine a
difference. This supports our conclusion that our
findings are characteristic of cystic fibrosis and not
the greater degree of impairment of pulmonary
function.
Summary
Limitations
This study is a review of cardiovascular findings in
a population of patients under evaluation for lung
transplantation. Because of the advanced degree of
the lung disease in these patients, the results of this
study cannot necessarily be extrapolated to the general population of patients with cystic fibrosis without further study. Further study of a broader age
range of patients may allow demonstration of an
association between diastolic parameters and age in
our study.
In this study, patients with cystic fibrosis were
found to have normal left ventricular systolic function but significant diastolic dysfunction as evidenced by radionuclide ventriculography (percentage of filling at 50% of diastole, atrial filling
contribution, and time to peak filling/R-R interval
ratio). Progressive myocardial fibrosis as described in
previous pathology reports of cystic fibrosis and/or
ventricular interdependence may partially explain
this finding.
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2 Wiebicke W, Artlich A, Gerling I. Myocardial fibrosis: a rare
complication in patients with cystic fibrosis. Eur J Pediatr
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Clinical Investigations