Cardiomyopathy

Study objectives: Cardiac sympathetic nerve dysfunction is related to poor clinical outcome in patients with several different heart diseases. However, it is not clear whether cardiac sympathetic nerve activity is useful for predicting the onset of congestive heart failure (CHF) in patients with hypertrophic cardiomyopathy (HCM). The aim of this study was to examine the prognostic value of performing [sup.123]I-labeled metaiodobenzylguanidine (MIBG) scintigraphy in patients with HCM in comparison with other conventional prognostic variables.

Methods: [sup.123]I-labeled MIBG images were obtained from 84 HCM patients without prior CHF. After measurement of cardiac function, the patients were followed up for 9 to 86 months in our hospital.

Results: According to the cutoff values for the heart/mediastinum ratio (H/M) on delayed images of control subjects (ie, mean--1 and 2 SDs), the patients were subdivided into the following three groups: group A (H/M, > 2.11; 34 patients); group B (H/M, < 1.86 to [less than or equal to] 2.11; 30 patients); and group C (H/M, [less than or equal to] 1.86; 20 patients). The prevalence of CHF was 0% in group A, 3.3% in group B, and 55.0% in group C. Kaplan-Meier analysis showed a significant difference in the prevalence of CHF among the three groups. Multivariate analysis using the Wald [chi square] test revealed that the delayed H/M was the most powerful predictor of CHF among the variables.

Conclusion: Cardiac sympathetic nerve activity is useful for predicting the onset of CHF in patients with HCM.

Key words: congestive heart failure; hypertrophic cardiomyopathy; [sup.123]I-labeled metaiodobenzylguanidine

Abbreviations: CHF = congestive heart failure; HCM = hypertrophic cardiomyopathy; H/M = heart/mediastinum ratio: MIBG = metaiodobenzylguanidine; NYHA = New York Heart Association; ROI = region of interest; WOR = washout rate

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Congestive heart failure (CHF) caused by left ventricular dilatation and systolic dysfunction is an important prognostic determinant as well as a predictor of sudden cardiac death in patients with hypertrophic cardiomyopathy (HCM). (1-5) Moreover, patients with CHF due to HCM usually have a very poor prognosis and are resistant to medical therapy. (6) In addition, medical therapy for CHF is generally contraindicated for patients with uncomplicated HCM, so it is often difficult to know when to initiate treatment for CHF due to HCM. Appropriate therapy before CHF becomes obvious may improve the prognosis of patients with HCM. However, to our knowledge, there are no effective clinical tools for predicting the onset of CHF in patients with HCM.

The assessment of myocardial sympathetic nerve activity by [sup.123]I-labeled metaiodobenzylguanidine (MIBG) myocardial scintigraphy is known to be useful for predicting the onset of CHF in patients with several different heart diseases, such as dilated cardiomyopathy, valvular heart disease, ischemic heart disease, and essential hypertension. (7-10) In patients with HCM, myocardial sympathetic nerve dysfunction, as demonstrated by [sup.123]I-MIBG myocardial imaging, appears to reflect myocardial hypertrophy and damage. (11-13) We also have reported that myocardial sympathetic nerve activity correlates well with left ventricular systolic function, and that defects found by [sup.123]I-MIBG scintigraphy appeared earlier in HCM patients than did myocardial perfusion abnormalities assessed by [sup.201]Tl myocardial scintigraphy. (13) However, there have been no data concerning the prognostic value of [sup.123]I-MIBG scintigraphy in assessing patients with HCM.

The present study was performed to examine the prognostic value of [sup.123]I-MIBG scintigraphy in comparison with other conventional variables for the prediction of CHF due to progression from typical HCM to dilated cardiomyopathy-like features in patients with HCM.

MATERIALS AND METHODS

Subjects

A total of 84 patients with HCM were selected from 95 consecutive HCM patients in whom [sup.123]I-MIBG myocardial scintigraphy was performed between May 1993 and August 2000. Eleven patients who had diabetes mellitus, ischemic heart disease, massive valvular heart disease, or chronic renal failure (ie, serum creatinine level, > 1.5 mg/dL) were excluded from this study. The diagnosis of HCM was made by echocardiography based on the World Health Organization/International Society and Federation of Cardiology definitions of cardiomyopathies. (14) The criteria for CHF diagnosis in this study were defined as the clinical symptoms of New York Heart Association (NYHA) functional class III or IV with lung edema and a dilated left ventricle.

None of the patients had a history of allergy to iodine or were taking drugs known to interfere with [sup.123]I-MIBG uptake. The 84 patients with HCM consisted of 67 men and 17 women with a mean ([+ or -] SD) age of 63 [+ or -] 11 years (age range, 28 to 87 years). The mean follow-up period for these patients was 48.1 [+ or -] 24.3 months (range, 9 to 86 months). Fifteen patients were of the obstructive type, with pressure gradients of > 30 mm Hg without provocation, (15) and 69 patients were of the nonobstructive type. Concerning clinical symptoms, 38 patients had a history of chest pain or oppressive feelings in the chest, 23 patients had a history of dyspnea, and 13 patients had a history of syncope. Eleven patients had a history of mild hypertension. Eight patients had a history of paroxysmal atrial fibrillation, and 8 patients had persistent atrial fibrillation. All patients who had chest pain had a healthy coronary artery with no evidence of spasm, as revealed by angiography. Fifteen subjects (10 men and 5 women; mean age, 62 [+ or -] 9 years) who had no cardiac or systemic diseases were entered into the study as healthy control subjects for [sup.123]I-MIBG scintigraphy. Written informed consent for performing the protocol was obtained from each patient.

[sup.123]I-MIBG Myocardial Scintigraphy

[sup.123]I-MIBG scintigraphy was performed according to the previously reported method. (10) On the day of [sup.123]I-MIBG scintigraphy, patients were instructed to have no breakfast and to continue fasting until the end of the last imaging session. A 11-mBq close of [sup.123]I-MIBG (Daiichi Radioisotope Laboratory; Tokyo, Japan) with a specific activity of 1,665 to 2,035 mBq/mg was administered IV, and early and delayed images were obtained 15 min and 5 h after the administration of [sup.123]I-MIBG. To quantify the myocardial accumulation of [sup.123]I-MIBG, we used the anterior planar projection images. A region of interest (ROI) was set on the entire heart, and a square ROI, usually 10 x 10 pixels in size, was set on the mediastinum on both the early and delayed images (Fig 1). The counts per pixel were measured for each ROI, and the heart/mediastinum ratio (H/M) for [sup.123]I-MIBG activity was calculated. The myocardial washout rate (WOR) of [sup.123]I-MIBG was determined as the percent change in activity from 15 min to 5 h after the isotope administration.

[FIGURE 1 OMITTED]

ECG Measurement

Standard ECGs were recorded with patients in the supine position, We calculated the voltage for S[V.sub.1] + R[V.sub.5] (16) and the total 12-lead QRS voltage (17) as the ECG markers of left ventricular hypertrophy. All measurements were performed by one investigator who was not aware of the backgrounds of the patients.

Echocardiographic Measurement

Echocardiographic studies were performed with an echocardiograph (model SSD-870 or SSD-2200; Aloka Inc; Tokyo, Japan) that used a 3.5-MHz transducer. The left ventricular end-diastolic dimension, end-systolic dimension, interventricular septal thickness, and left ventricular posterior wall thickness were measured according to the recommendations of the American Society of Echocardiography. (18) Fractional shortening was calculated from the following equation: ([end-diastolic dimension--end-systolic dimension]/end-diastolic dimension) x 100. All measurements were performed by one investigator who was not aware of the backgrounds of the patients.

Statistical Analysis

Statistical analysis was performed using computerized statistical software (StatView; SAS Institute Inc, Cary, NC). The data are expressed as the mean [+ or -] SD. The H/M values of [sup.123]I-MIBG on delayed images for patients with HCM and for healthy subjects were compared using the Student t test. Categoric variables (ie, clinical type of HCM, symptoms, history, and medications) were compared with the Fisher exact test and the [chi square] test. Other comparisons among the three groups were carried out using one-way analysis of variances with subsequent Scheffe multiple-range tests. Univariate correlation was analyzed using the Pearson correlation coefficient. We selected 10 independent predictors (ie, age, heart rate, NYHA class, clinical type, H/M on delayed image, WOR, left ventricular diastolic dimension, left: ventricular systolic dimension, fractional shortening, and left ventricular wall thickness) that might affect the prognosis according to clinical, cardiac function, and scintigraphic parameters, and the statistical potential of each of these predictors was analyzed by multivariate analysis using the Wald [chi square] test for the Cox proportional hazards model, A survival curve estimate was created by the Kaplan-Meier method and was analyzed by the log-rank test. A p value of < 0.05 was considered to be significant.

RESULTS

Baseline Characteristics of the Patients

The mean H/M of [sup.123]I-MIBG on the delayed image was decreased in HCM patients compared with healthy subjects (2.05 [+ or -] 0.29 vs 2.36 [+ or -] 0.25, respectively; p < 0.001). According to the cutoff values of the H/M on the delayed image, which was selected by referring to the mean--1 and 2 SDs for the control subjects, 34 of the 84 patients were subdivided into group A (H/M, > 2.11), 30 patients into group B (H/M, < 1.86 to [less than or equal to] 2.11), and 20 patients into group C (H/M, [less than or equal to] 1.86).

The profiles of these three groups are shown in Table 1. The mean follow-up period in group C was shorter than those in groups A and B. However, when patients with CHF were excluded from the analysis there were no significant differences in the mean duration of the follow-up periods among the three groups (group A, 57.7 [+ or -] 22.9 months; group B, 46.2 [+ or -] 23.9 months; group C, 40.2 [+ or -] 23.7 months). Heart rates were higher in group C than in group B. However, there were no significant differences in any of the other parameters described in Table 1.

[sup.123]I-MIBG, ECG, and Echocardiographic Findings

Table 2 shows the comparisons of indexes measured by [sup.123]I-MIBG scintigraphy, electrocardiography, and echocardiography. The mean H/M values on the delayed image in groups A, B, and C were 2.3 [+ or -] 0.2, 2.0 [+ or -] 0.0, and 1.7 [+ or -] 0.2, respectively. The H/M value on the early image was lower ill group A than those in groups B and C. Myocardial WOR was higher in group C than in groups A and B. The left ventricular end-systolic dimension was larger in group C than in groups A and B. Left ventricular fractional shortening was higher in group A than in group C. There were no significant differences in the voltage of R[V.sub.5] + S[V.sub.1], total 12-lead QRS voltage, left ventcicular end-diastolic dimension, and left ventricular wall thickness among the three groups. Fractional shortening correlated positively with the H/M on the delayed image (r = 0.46; p < 0.0001).

Incidence of CHF During the Follow-up Periods

During the follow-up periods, CHF occurred in 12 patients (14.3%). No patient had CHF in group A, whereas the prevalence of CHF was 3.3% in group B and 55.0% in group C. The baseline characteristics of the patients with CHF are shown in Table 3. Eleven of the 12 patients were of the nonobstructive type including 2 of" the apical type.

Relationship Between Myocardial Sympathetic Nerve Activity and CHF

As shown in Table 4, multivariate analysis revealed that the delayed H/M and fractional shortening were significant predictors for the onset of CHF among the 10 parameters. The other parameters, including age, heart rate, NYHA class, clinical type, WOR, left ventricular diastolic dimension, left ventricular systolic dimension, and left ventricular wall thickness, were not significant predictors for CHF in patients with HCM. In addition, the Wald [chi square] tests and estimated odds ratios indicated that the delayed H/M was the most powerful independent predictor among these parameters.

Figure 2 shows the estimated survival curve for CHF (Kaplan-Meier analysis) in the three groups. There was a significant difference in the prevalence of CHF between group C and the other two groups. Figure 3 shows the relationship between the H/M on the delayed image and the time from the measurement of [sup.123]I-MIBG scintigraphy to the onset of CHF. As shown in Figure 3, there was a strong positive correlation between the two variables.

[FIGURE 2-3 OMITTED]

DISCUSSION

This study demonstrates for the first time that delayed H/M and fractional shortening are significant predictors for the onset of CHF in patients with HCM. Of these two parameters, cardiac sympathetic nerve activity on the delayed image was the strongest predictor for the onset of CHF.

HCM is characterized by a hypertrophied and nondilated left ventricle with hyperdynamic contraction and impaired diastolic filling. However, this pattern of the left ventricle gradually hut progressively changes clinical course in many patients. In the clinical setting, important prognostic predictors for sudden cardiac death and end-stage CHF have been investigated in HCM. McKenna ct al (1) reported that sudden and unexpected cardiac death contributes to about half of the causes of death in HCM patients, whereas the progression of typical HCM to left ventricular dilatation and dysfunction occurs in only about 10% of patients. (2) Other investigators (19,20) also showed that CHF occurred in 4 to 7% of patients with HCM. We have also reported that CHF with lung edema occurred in only 12 of 210 patients (5.7%), but in the remaining 198 patients the mean left ventricular dimension was significantly increased from 42.6 [+ or -] 6.7 to 50.8 [+ or -] 11.6 mm, and the total QRS voltage was significantly decreased from 39.7 [+ or -] 10.9 to 21.3 [+ or -] 10.7 mV during a 12-year follow-up period. (6) Thus, the incidence of CHF may increase with a longer follow-up period. Hecht et al (21) emphasized that the coexistence of end-stage heart failure and sudden death in HCM patients might be more common than has been perceived. In addition, they also reported that end-stage heart failure was more often observed in older patients with HCM. Therefore, CHF may be a more important outcome than has been accepted up to now. Usually, CHF due to HCM has a very, poor prognosis, and patients are resistant to medical therapy. (6) Thus, the early detection and prevention of the progression of HCM to CHF are important and essential in HCM patients. However, it is usually difficult to detect the progression to CHF at an early stage by conventional examinations, such as ECG and echocardiogram.

It is well-known that [sup.123]I-MIBG scintigraphy is available for the noninvasive assessment of myocardial sympathetic nerve innervation and activity, which is useful for predicting cardiac death and other events in patients with several different heart diseases and conditions. (7-10) It has been reported that [sup.123]I-MIBG scintigraphy reflects the presence of myocardial hypertrophy and damage in HCM patients. (11-13) In the present study, there were no significant differences in the indexes of left ventricular hypertrophy assessed by electrocardiography and echocardiography among the three groups. Thus, the decreased [sup.123]I-MIBG activity observed in the present study is thought to be related to myocardial damage. Prior to the present study, some investigators have reported on the prediction of sudden cardiac death in HCM patients on the basis of clinical signs, presence of arrhythmia, and echocardiographic findings, (22-25) but not all studies have found these prognostic indicators to be useful for the prediction of CHF in HCM patients. The present study showed that cardiac sympathetic nerve function correlated more specifically with the onset of CHF than with other hemodynamic predictors in HCM patients.

The exact mechanisms of the progression from typical HCM to dilated cardiomyopathy-like features remain to be determined. However, some reports using myocardial scintigraphy have provided evidence that myocardial ischemia is deeply related to the changes seen in this process. Several investigators have reported (26-28) that transient defects of [sup.201]Tl scintigraphy and angina were noted in about half of HCM patients with healthy coronary arteries. One reason for this may be a relative decrease in the vascular bed relative to the cellular mass associated with the involvement of small coronary artery disease. In addition, Nagata et al (4) and Hamada et al (5,29) reported a persistent elevation of cardiac enzymes and defects in [sup.201]Tl scintigraphy in HCM patients who developed dilated cardiomyopathy-like features. Thus, myocardial damage due to continuous myocardial ischemia seems to be deeply related to the progression toward the dilated phase of HCM. Usually, defects seen in [sup.123]I-MIBG scintigraphy in the acute phase of ischemic heart disease are wider than the defects seen in [sup.201]Tl myocardial scintigraphy. (30) Moreover, we have reported (12,13) that the appearance of [sup.123]I-MIBG defects preceded myocardial perfusion abnormalities assessed by [sup.201]Tl scintigraphy in HCM patients. Taking all of the evidence into consideration, we think that the reduced [sup.123]I-MIBG activity results from sympathetic denervation as a consequence of continuous myocardial ischemia primarily due to small-vessel coronary artery disease. (2) Thus, [sup.123]I-MIBG scintigraphy may be able to reflect myocardial injury more sensitively than other examinations.

A significant association was found between the H/M and both fractional shortening and time to CHF. Kaplan-Meier survival curves revealed that the prognosis became poor in patients with a low H/M. These results indicate that myocardial [sup.123]I-MIBG scintigraphy is very, useful for evaluating the myocardial condition of HCM patients. Because the mean follow-up period from [sup.123]I-MIBG scan to CHF in these i2 patients was 31 [+ or -] 18 months, the screening ability may be relatively poor. However, it usually takes a long time to progress from typical HCM to dilated cardiomyopathy-like features. (6) Thus, we believe that [sup.123]I-MIBG scintigraphy can predict the occurrence of CHF in patients with HCM by detecting subclinical myocardial damage before the appearance of abnormal left ventricular geometry and function. In conclusion, the delayed H/M may be a valuable and reliable marker in predicting the onset of CHF in patients with HCM.

* From The Second Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime, Japan.

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Manuscript received July 29, 2003; revision accepted March 9, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Go Hiasa, MD, Department of Cardiology. Kitaishikai Hospital, Tokunomori 2632-3, Ozu, Ehime 795-8505, Japan: e-mail: ghiasa@cnw.ne,jp

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