Doppler Echocardiographic Detection of Left Ventricular Diastolic Dysfunction in Patients With Pulmonary Sarcoidosis

Doppler Echocardiographic Detection of Left Ventricular Diastolic Dysfunction in Patients With Pulmonary Sarcoidosis* Gerard]. Fahy, MB; Thonws Marwick, MBBS; Charles]. McCreery, MB; Peter]. Quigley; and Brian]. Maurer Study objective: To determine the prevalence of left ventricular diastolic dysfunction in patients with biopsy specimen-proved pulmonary sarcoidosis without clinical evidence of cardiac disease. Design: A cross-sectional study. Setting: A large tertiary care university teaching hospital. Patients and control subjects: Fifty consecutive subjects had biopsy specimen-proved pulmonary sarcoidosis without suspected cardiac involvement. Those with other conditions known to affect diastolic function were excluded. The control group comprised 30 healthy hospital workers. Interventions: Clinical examination, 12-lead ECG, and combined echocardiographic/phonocardiographic examination. Measurements: Indexes of left ventricular diastolic function, including isovolumic relaxation time, peak velocity of early (E) and late (A) ventricular tilling, deceleration rate of early diastolic flow, and the sum of the time velocity integrals of E and A were obtained in each patient and control subject. Systolic function was determined using a modification of Simpson's rule.

Sarcoidosis is a multisystem disorder of unknown etiology characteiized by infiltration of several organ systems by noncaseating granulomas. The lungs, skin, and eyes are most commonly affected. It is an uncommon disease with a prevalence of approximately 20/100,000. 1 Cardiac involvement, first recognized in 1929, was considered an uncommon complication until relatively recent postmortem studies demonstrated cardiac involvement in up to 27% of cases. 2 It is important to detect sarcoid cardiomyopathy as early a~ possible as it is associated with considerable morbidity and mortality that is often sudden3 and is potentially treatable. 4-8 Clinical detection is hampered because of the similarity of symptoms and signs of pulmonary and cardiac infiltration.2 Two-dimensional echocardiography (2-D echo) can detect abnormalities in up to 31% of patients with clinically suspected cardiac sarcoido*From th e Department of Cardiolozx, University College and St. Vincent's Hospital, Dublin, Ireland (Drs. Fahy, McCreery, Quigley, and Maurer), and Department of Cardiology, Cleveland Clime Fou ndation (Drs. Fahy and Manvick), Cleveland, Ohio. Manusclipt received March 15, 1995; revision accepted June 21. 62

Results: Diastolic dysfunction was present in 7 (14%) patients, 6 of whom had normal systolic function and normal two-dimensional echocardiographic examination. Those with diastolic dysfunction had a longer duration of illness (15 ± 7 vs 6±5 years; p=0.0004), were significantly older (52±11 vs 38±9 years; p=0.0009), and had higher systolic BP (130± 13 vs 117 ± 12 mm Hg; p=0.01) than the sarcoid patients with normal diastolic function. Conclusions: These results demonstrate a significant prevalence of left ventricular diastolic dysfunction in patients with pulmonary sarmidosis. The cause of this abnormality may he a subclinical sarcoid cardiomyopathy. (CHEST 1996; 109:62-66)

BBB=hundle branch block; 2-D echo=two-dimensional echocardiography

Key words: diastolic dysfunction; Doppler; echocardiography; sarcoid cardiomyopathy

sis, 9.l 0 but this technique is limited by a relatively high rate of unsatisfactory image quality. Doppler echocardiography provides a reliable, safe, noninvasive means of assessing ventricular diastolic function 11 .1 2 that may precede systolic or 2-D echo abnormalities in many cardiomyopathic states. 13· 16 We used Doppler echocardiography to detect the prevalence of left ventricular diastolic dysfunction in an outpatient population with biopsy specimen-proved pulmonary sarcoidosis. METHODS

Patients and Control Suf1ects

Fifty-five consecutive outpatients with transbronchial biopsy specimen-proved pulmonary sarcoidosis were recruited from a university hospital pulmonary sarcoid clinic. All patients gave informed consent and the study was approved b y the local ethics committee. Patients were included if aged between 16 and 70 years and had biopsy specimen-proved pulmonary sarmidosis of any duration. Patients were excluded if any of the following potential causes of ventlicular diastolic dysfunction were present: systemic hypertension, ischemic or structural heart disease, cor pulmonale, diabetes mellitus, or alcoholism. Patients with cardiac rhythms known to affect Doppler-delived parameters of diastolic function Clinical Investigations

Table 1-Echocardiographic Indexes of Sarcoid (S) Patients and Control (C) Subjects*

Age, yr Sex, female:male Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, beats/min E, cm/s A, cmls E/A TVI, em EfiVI, s E-F, cm·s- 2 IVRT, ms

S (n=50)

C n=30) (

p Value

40::'::10 32:18 119::'::13 76::'::9 72::'::12 63::'::13 45::'::12 1.5::'::0.5 13::'::2 5::'::0.8 384::':: 120 79::'::13

39::'::9 16:14 123::'::15 75::'::9 66::'::13 66::'::10 42::'::7 1.6::'::0.35 14::'::2 5::'::0.6 405::'::78 75::'::8

NS NS NS NS 0.03 NS NS NS NS NS NS NS

*A=peak velocity of late ventricular filling; E=peak velocity of early left ventricular filling; E- F =rate of deceleration of early filling wave; TVI=time velocity integral; IVRT =isovolumic relaxation time; MS=milliseconds. such as atrial fibrillation or sinus tachycardia were also excluded . Of the 55 patients, 5 were excluded because of either sinus tachycardia (3 patients) or unsatisfactory image acquisition (2 patients). All patients were assessed clinically and resting 12-lead ECGs were recorded from all patients. Control subjects were selected from a population of hospital workers without a history of cardiovascular disease, who had normal results of clinical examination and 12-lead ECGs. All patients and control subjects were white. Echocardiographic Study All patients and 30 control subjects were examined in the left lateral semirecumbent position using a scanner (Sonos 1000 Scanner equipped with a 2.5-MHz probe; Hewlett-Packard; Andover, Md). Two-dimensional, M-mode, continuous wave, and color flow Doppler echocardiography was performed from standard parasternal and apical windows in long and short axes. Pulsed Doppler echocardiographywas performed from an apical four-chamberview with the sample volume placed at the level of the mitral valve leaflet tips with the cursor orientated parallel to an imaginary line bisecting the left ventricle from apex to mitral valve. The position of the sample was adjusted to obtain a mitral inflow pattern with maximal early diastolic velocity and optimal signal-to-noise ratio. Simultaneous recordings of standard lead II of the ECG and phonocardiography from the aortic area were a sl o performed. All examinations were recorded on videotape using a system capable of frame-by-frame bidirectional playback. Simultaneous recording of mitral inflow pattern and phonocardiography was made on paper at a paper speed of 100 mm/s. Measurement All measurements were made over four cardiac cycles using software incorporated into the system (Hewlett-Packard), apart from the isovolumic relaxation time that was measured directly from

the paper printout. The isovolumic relaxation time was defined as the time from the first high-frequency component of the aortic valve closure sound to the beginning of mitral inflow detected by pulsewave Doppler echocardiography. The following M-mode parameters were measured in standard fashionP septal and posterior left ventricular wall thickness, left ventricular diameter at end diastole and systole, and left attial size. Left ventricular ejection fraction was calculated using a modification of Simpson's rul e .18 The following Doppler echocardiographiclphonocardiographic indexes of left ventricular diastolic function were also measured: isovolumic relaxation time, peak velocity of early (E) and late (A) diastolic filling, sum of time velocity integrals of E and A (TVI), and rate of deceleration of early diastolic flow (E-F). The following values were then derived: E/A and EfiVI. Diastolic dysfunction was defined as the presence of at least two abnormal unrelated indexes of diastolic function. The normal range for each index of diastolic function was defined as the mean::'::SDs of the control group. Statistics Group data are expressed as mean::'::SD. Parametric data were compared using the unpaired Student's t test. The x2 test was used to analyze categorical variables and the Spearman rank correlation test was used to detect relationships between variables. Statistical significance was defined as a p value less than 0.05. R ESULTS

Clinical Features

There were no significant differences in age or gender between the sarcoid (40±10 years; 32 female) and control (39±9 years; 16 female) groups. All subjects were normotensive and no significant differences in systolic or diastolic BPs between these two groups were observed. There was a small but significant difference (p=0.03) in heart rate between the sarcoid (72 ± 12 beats per minute) and control (66± 13 beats per minute) groups (Table 1). Results of cardiovascular examination were nonnal in all patients with no evidence of hypertension, ventricular dysfunction, mitral regurgitation, or pericarditis. Standard 12-lead ECG was normal in all sarcoid patients except one with diastolic dysfunction (case 2 in Table 2) who had left bundle branch block (BBB) with a normal PR interval. Doppler Echocardiography

Doppler echocardiographic evidence ofleft ventricular diastolic dysfunction was detected in 7 (group A) of 50 patients. Group A patients had a longer duration

Table 2-Clinical Characteristics of Patients With Left Ventricular Diastolic Dysfunction Case/Sex/Age, yr 1/F/52 2/M/49 3/F/39 4/M/51 5/F/69 6/M/63 7/F/39

Duration of Sarcoid, yr 12 ll

13 18 6 28 15

Medication None Prednisolone, 2.5 mgld Beclomethasone inhaler Prednisolone, 5 mgld Prednisolone, 5 mgld Prednisolone, 5 mgld None

Symptoms (NYHA* Class) Dyspnea Dyspnea Dyspnea None Dyspnea Dyspnea None

(II ) (I) (II) (II)

(III )

BP, mm Hg

Heart Rate, Beats/min

130/80 110/50 140/80 150/84 142174 140/80 12ono

77 82 94 57 66 100 70

*NYHA=New York Heart Association. CHEST /109/1/ JANUARY, 1996

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Table 3-Clinical Characteristics of Patients With (A) and Without (B) Diastolic Dysfunction

Age, yr Sex, female :male Duration of sarcoid, yr No. requiring steroids Symptoms Systolic BP, mm J-Ig Diastolic BP, mm Hg Heart rate, beats/min

Group A (n=7)

Group B (n=43)

p Value

52:!: 11 4:3 15:!: 7 3 5 130:!:13 77:!:4 78 :!: 15

38:!:9 25:18 6:!:5 15 22 117:!:12 76:!:12 71 :!: 11

0.0009 NS 0.0004 NS NS 0.01 NS NS

of illness (15±7 vs 6±5 years; p=0.0004), were significantly older (52± 11 vs 38±9 years; p=0.0009), and had a higher systolic BP (130± 13 vs 117 ± 12 mm Hg; p=0.01) than the other sarcoid patients with normal diastolic function (group B) (Table 3). There were no differences in symptoms or steroid requirements between patients in group A and B (Table 3). Of the group A patients, one had four, three had three, and three had two abnormal unrelated indexes of diastolic function (Table 4). There were no differences detected in diastolic function between the sarcoid and control groups as a whole when the mean values of each echocardiographic index were compared (Table 1). There was no correlation between age, systolic BP, or ejection fraction and any of the indexes of diastolic function in the sarcoid group.

Two- Dimensional Echocardiography Two-dimensional echocardiography was normal in all patients except one who demonstrated septal dyskinesis, a subnormal left ventricular ejection fraction (50% ), and left BBB. Left ventricular septal and posterior wall thickness was normal in aU patients with no significant difference between sarcoid patients with or without diastolic dysfunction (Table 5). Left ventricular dimensions were normal in all patients but significantly larger in patients with diastolic dysfunction (Table 5). Group A patients had a lower mean left

ventricular ejection fraction compared with group B (58±6% vs 64±4%; p=0.0007). Left atrial size was normal in all subjects and was not significantly different among the two sarcoid groups. No patient had a pericardia! effusion or myocardial echo densities. Color flow echocardiography was normal in all patients with no evidence of mitral regurgitation. DISCUSSION

Sarcoid cardiomyopathy is associated with considerable morbidity and mortality. Its clinical manifestation is dependent on the site and extent of granulomatous infiltration; the most common modes of presentation in order of frequency are complete heart block, ventricular arrhythmias, cardiac failure, sudden death, first-degree heart block or BBB, supravenhicular arrhythmias, mitral regurgitation, and pericarditis.4 Effective treatment, consisting of corticosteroids, cardiac pacing, antiarrhythmic drugs, and implantable defibrillators, is available to prevent progression and possibly reverse the underlying process, and treat its complications. 4·8 It is therefore imperative to diagnose this disease as early in its course as possible. However, clinical detection of this disease is unreliable as pulmonary and cardiac granulomatous infiltration is associated with similar symptoms and signs. 2 Cardiac sarcoidosis is considered uncommon, and thus, early diagnosis may be further hampered by failure of the

Table 4-Echocardiographic Features of Sarcoid Patients With Diastolic Dysfunction* Dopple r Ecbocardiography

2-D Echo

Case

LA, mm

EDD , mm

ESD , mm

LVEF, %

Septum, mm

PW, mm

IVRT, ms

E, cm/s

A, cm/s

1 2 3 4 5 6 7 Mean :!: SD

32 32 20 41 29 32 35 31 :!:6

52 49 49 53 47 55 54 51 :!:3

26 40 34 34 36 43 43 36.5 :!:6

61 50 55 55 58 56 68 58:!:6

7 8 8 8.5 8 ll 7 8.6:!:1.5

6 .5 8 7 10 7.5 ll 7 8:!:1.7

97.5 1 109 1 90 92.5 1 105 1 67.5 76 91 :!: 15

49 44 1 70 61 28' 39 1 39 1 47 :!: 14

60 1 55

so'

58.5 1 50 54 45.5 57 :!: 11

TVI, em

EITVI,

EIA

E-F, C·ms- 2

0.8 1 0.8 1 0.8 1 1 0.5 1 0.7 1 o.85 1 0.8 ± .1

13.5 ll 11 15.5 9.75 8.25 1 9.6 1 11±2

3.6 1 4 6.5 1 3.9 2.9 1 4.7 4 4±1

235 1 255 513 384 104 1 1661 189 1 260±140

*EDD=left ventrkular end-diastolic diamete r; ESD=Ieft ventricular end-systolic diameter; LA=left atrial diameter; PW =posterior left ventricular wall thickness; LVEF=Ieft ventricular ejection fraction ; MS=milliseconds. 1Denotes an abnormal result.

64

Clinical Investigations

Table 5-Echocardiographic Features of Patients With Sarcoidosis

LVEF, % LA diameter, mm IVRT, ms* E, cm/s A, cm/s E/A TVI, em Eff\II, s E-F, cm·s- 2 Septal thickness, mm LV PW thickness, mm LVEDD , mm LVESD , mm

Group A (n=7)

Group B (n=43)

p Value

58::':6 31::':6 91::':15 47::':14 57::':11 0.8::':0.1 11::':2 4::':1 260::':140 8.6::':1.4 8::':1.7 51::':3 36::':6

64::':4 33::':5 77::':11 66::':11 43::':11 1.6::':0.4 13::':2 5::':0.8 400::':110 8::':1.2 8::': 1.4 49 ::':3 33::':4

0.0007 NS 0.004 0.0002 0.002 0.0001 0.02 0.03 0.003 NS NS 0.05 0.04

*MS=milliseconds.

physician to consider its presence. This is highlighted by one study that revealed that in patients with autopsy-proved cardiac sarcoid, the antemortem diagnosis was made in onlv 65% of cases. 2 It is therefore not surprising that previous investigators have attempted to detect evidence of early sarcoid cardiomyopathy using a variety of diagnostic tests. However, most have suffered from either poor sensitivity or specificity. 19-21 Some workers have used 2-D echo for this purpose and have demonstrated abnormalities in 14 to 31% of cases. 9 •10·21 In the present study, 2-D echo was abnormal in only one patient (2% ). There were no examples of pericardial effusion, mitral regurgitation, or myocardial echo densities as seen in previous studies. The reason for this difference between the present and previous studies is unclear. One possible explanation may be that some of the previous investigations were retrospective so that echocardiography was performed only in patients with a high clinical suspicion of cardiac disease, therefore tending to overestimate the true prevalence of 2-D echo abnormalities in patients with sarcoidosis. The use of Doppler echocardiography in the detection of sarcoid cardiomyopathy was recently reported. 22 These workers concluded that 50% of patients with systemic sarcoidosis with clinically normal hearts had evidence of left ventricular diastolic dysfunction. However only ten patients and ten control subjects, all of whom were women, were studied and the critelia for defining diastolic dysfunction were not as stringent as ours, tending to increase the sensitivity and reduce the specificity of their test. In the present study, left ventricular diastolic dysfunction was detected using Doppler echocardiography in 7 of 50 consecutive patients witl1 unsuspected cardiac disease. It is likely that these patients have a subclinical sarcoid cardiomyopathy as patients with other potential causes of diastolic dysfunction were not

studied. In addition, left ventricular ejection fraction, although normal in all but one patient, was significantly less in group A than B and left ventricular dimensions were also greater for group A patients, fmther suggesting that this group had an early subclinical cardiomyopathy. There was no evidence of hemodynamic compromise in these patients as the frequency and severity of dyspnea and left atrial size among groups A and B was not significantly different. The pattern of diastolic dysfunction in these patients is more consistent with an abnormality of active relaxation rather than with diminished compliance of the left ventricle. This was manifest by a prolonged isovolumic relaxation time in four of the seven patients and a reversal of the normal E:A ratio in six patients. No patient had evidence of a restrictive pattern ofleft ventricular filling. In addition, left ventricular wall thickness and left atrial size were normal in these patients. This is similar to cardiac amyloidosis in which early infiltration is manifest only by relaxation abnormalities with changes in compliance developing at a later stage in the disease. 16 It is not clear why these patients demonstrated this pattern of abnormality. At least three explanations are possible. First, these patients may have had infiltration of noncaseating granulomas in the myocardial interstitium, not severe enough to allow detection by 2-D echo, which in some way interfered with the active adenosine triphosphate-dependent phase of venhicular diastole. Second, these patients may have had a coronary microangiopathy with consequent ischemia, which is known to cause this particular diastolic abnormality. 23 This abnormality of the coronary circulation has been desclibed in some (usually black) patients with sarcoid and is manifest by anginal-type chest pain and thallium 201 scintigraphic myocardial defects in the presence of normal epicardial coronary arteries. 21 ·24 However, none of our patients (all caucasian) experienced anginal-type chest pain. Third, it is possible that the differences noted in diastolic function were not due to intrinsic myocardial properties but were due to the effects of confounding factors . Group A patients were significantly older and had significantly higher systolic BP than those in group B; both factors tend to influence Doffler-delived indexes of diastolic ventlicular function. 0 •26 However, the mean age difference between groups A and B was small and in one study, no significant differences in diastolic indexes were demonstrated between two groups with ages similar to those of our groups. 27 Furthermore, systolic BP differences were small and no differences in ventricular wall thickness were observed between tl1e two groups, suggesting that the difference in systolic BP was not important. We acknowledge that our study is limited by the absence of histologic proof of cardiac granulomatous CHEST / 109 / 1 / JANUARY, 1996

65

infiltration in patients with diastolic dysfunction; more definite evidence of sarcoid cardiomyopathy will depend on clinical and echocardiographic evidence of disease progression in these patients or by subjecting them to endomyocardial biopsy. In conclusion, there is a significant prevalence of abnormal left ventricular diastolic function in patients with sarcoidosis without suspected cardiac involvement. The significance of these abnormalities is unknown and therefore the usefulness of Doppler echocardiography as a screening tool in the detection of early sarcoid cardiomyopathy is uncertain and warrants further investigation. ACKNOWLEDGMENTS: We thank Francis O'Sullivan for excellent technic.al assistance; Professor M.X. Fitzgerald and Dr. Colm Quigley for refening patients for study; Allan Klein, MD, and Ser_gio Pinskl, MD, for manuscript review and helpful suggestions; ancfSiobhan Donian for excellent secretarial asststance. REFERENCES

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Clinical Investigations