**4. Discussion**

The principal finding of this study is that 123I-MIBG parameters, especially washout rate is useful for the risk stratification of sudden cardiac death in chronic heart failure patients without SVT. To the best of our knowledge, this is the first report to show a relation between sudden cardiac death and cardiac sympathetic nervous function using 123I-MIBG in heart failure patients without documented VT.

the most powerful predictor for sudden cardiac death in patients with mild-to-moderate

Risk Stratification of Sudden Cardiac Death by Evaluating Myocardial Sympathetic Nerve Activity Using Iodine-123…

http://dx.doi.org/10.5772/55615

237

Using 123I-MIBG, the role of impaired cardiac sympathetic innervations has been reported in patients with ventricular tachyarrhythmias. Akutsu et al. reported that impairment of cardiac sympathetic nervous system predicted recurrent ventricular tachyarrhythmic events in patients with a history of VT or fibrillation [22]. A prospective multicenter pilot study demonstrated that only defect severity of 123I-MIBG single photon emission computed tomography (SPECT) was predictive of inducibility of VT or fibrillation, whereas the conven‐

**4.4. 123I-MIBG kinetics and indication for implantable cardioverter defibrillator (ICD)**

A recent Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) [1] has proven the ef‐ ficacy of prophylactic ICD use for chronic heart failure patients without sustained VT and a history of ventricular fibrillation, not restricted in those with myocardial infarction. Since ICD is an expensive device, risk stratification is required to identify heart failure patients at high risk for sudden death without sustained VT. Based on the several guide‐ lines, prophylactic use of an ICD is recommended in patients with ventricular tachycar‐ dia who have severe systolic dysfunction. Nagahara et al. demonstrated that when combined with plasma BNP or cardiac function, impairment of cardiac sympathetic in‐ nervations would predict an ICD shock associated with lethal arrhythmias, contributing to identify suitable candidates for prophylactic ICD implantation [24]. Severely reduced left ventricular systolic function is a powerful predictor of sudden cardiac death. They concluded that 123I-MIBG scintigraphic evaluation for cardiac sympathetic innervations may be an option for screening patients at high risk for sudden cardiac death. Further‐ more, such abnormality had incremental and additive prognostic power when combined

Those recent reports mentioned above support our present results. Increased neuronal release of norepinephrine and decreased efficiency in the reuptake of norepinephrine through the uptake-1 mechanism contribute to the increased cardiac adrenergic drive, and lead to life

There are several limitations in this study. First, because of the retrospective study design, definite conclusions could not be drawn from our present data. BNP which is one of the important prognostic factors should be excluded in our multivariate analysis for prognostic determinants because of imperfect data. Second, the number of cardiac death was relatively small because the follow-up period was not long enough, so that more extensive case studies

threatening ventricular tachyarrhythmias in patients with heart failure.

and longer follow-ups are required to validate the results reported here.

heart failure [21].

tional index such as H/M was not [23].

with left ventricular dysfunction.

**4.5. Study limitations**

#### **4.1. MIBG parameters and heart failure**

Reduced pre-synaptic norepinephrine uptake and post-synaptic beta-adrenoreceptor density might contribute to the remodeling process of the left ventricle in the diseased heart [9]. Increased washout and decreased uptake of 123I-MIBG in the myocardium are related to the severity and prognosis of heart failure [10]. A recent meta-analysis including 18 studies with a total of 1755 patients reconfirmed that decreased uptake and increased washout of 123I-MIBG showed a poor prognosis in patients with heart failure. 123I-MIBG also has been used to assess the functioning of the pulmonary capillary endothelium under a variety of experimental or clinical conditions [11, 12]. Mu et al. speculated the increased lung uptake of 123I-MIBG in heart failure patients might be due to the enhanced permeability of the pulmonary endothelial cells [13]. We have demonstrated that the combined assessment of lung and heart 123I-MIBG uptake may help to predict future clinical outcome in patients with idiopathic dilated cardiomyopathy more accurately than myocardial evaluation alone [14].

#### **4.2. Autoantibody against the beta1 adrenoreceptor and heart failure**

We previously investigated the relationship between 123I-MIBG parameters and the anti-beta1 adrenoreceptor autoantibody level in chronic heart failure patients [15]. The autoantibodies stimulate the second extracellular domain of the beta1-adrenoreceptor like norepinephrine, and are associated with reduced cardiac function in patients with heart failure [16]. We have demonstrated that the anti-beta1-adrenoreceptor autoantibodies are closely associated with cardiac sympathetic nervous activity assessed by 123I-MIBG and cardiac event in patients with chronic heart failure [15]. Iwata et al. has reported that the autoantibodies predict VT and sudden death in patients with idiopathic dilated cardiomyopathy [17]. These results suggest that sudden cardiac death associated with ventricular tachyarrhythmias might be related to sympathetic nervous activity evaluated by 123I-MIBG scintigraphy.

#### **4.3. Cardiac sympathetic nervous function and sudden cardiac death associated with ventricular tachyarrhythmias**

Several electrocardiographic markers such as heart rate variability, single-averaged elec‐ trocardiogram, and QT dispersion have been proposed for the prediction of cardiac event in patients with heart failure [18-20]. Heart rate variability is a noninvasive tool for the condition of autonomic nervous activity and has been shown to predict future sudden cardiac death. Tamaki et al. reported a comparison of cardiac 123I-MIBG imaging with other electrocardiographic markers, and concluded that washout rate of 123I-MIBG was the most powerful predictor for sudden cardiac death in patients with mild-to-moderate heart failure [21].

Using 123I-MIBG, the role of impaired cardiac sympathetic innervations has been reported in patients with ventricular tachyarrhythmias. Akutsu et al. reported that impairment of cardiac sympathetic nervous system predicted recurrent ventricular tachyarrhythmic events in patients with a history of VT or fibrillation [22]. A prospective multicenter pilot study demonstrated that only defect severity of 123I-MIBG single photon emission computed tomography (SPECT) was predictive of inducibility of VT or fibrillation, whereas the conven‐ tional index such as H/M was not [23].

#### **4.4. 123I-MIBG kinetics and indication for implantable cardioverter defibrillator (ICD)**

A recent Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) [1] has proven the ef‐ ficacy of prophylactic ICD use for chronic heart failure patients without sustained VT and a history of ventricular fibrillation, not restricted in those with myocardial infarction. Since ICD is an expensive device, risk stratification is required to identify heart failure patients at high risk for sudden death without sustained VT. Based on the several guide‐ lines, prophylactic use of an ICD is recommended in patients with ventricular tachycar‐ dia who have severe systolic dysfunction. Nagahara et al. demonstrated that when combined with plasma BNP or cardiac function, impairment of cardiac sympathetic in‐ nervations would predict an ICD shock associated with lethal arrhythmias, contributing to identify suitable candidates for prophylactic ICD implantation [24]. Severely reduced left ventricular systolic function is a powerful predictor of sudden cardiac death. They concluded that 123I-MIBG scintigraphic evaluation for cardiac sympathetic innervations may be an option for screening patients at high risk for sudden cardiac death. Further‐ more, such abnormality had incremental and additive prognostic power when combined with left ventricular dysfunction.

Those recent reports mentioned above support our present results. Increased neuronal release of norepinephrine and decreased efficiency in the reuptake of norepinephrine through the uptake-1 mechanism contribute to the increased cardiac adrenergic drive, and lead to life threatening ventricular tachyarrhythmias in patients with heart failure.

#### **4.5. Study limitations**

**4. Discussion**

236 Cardiomyopathies

failure patients without documented VT.

**4.1. MIBG parameters and heart failure**

more accurately than myocardial evaluation alone [14].

**4.2. Autoantibody against the beta1 adrenoreceptor and heart failure**

sympathetic nervous activity evaluated by 123I-MIBG scintigraphy.

**4.3. Cardiac sympathetic nervous function and sudden cardiac death associated with ventricular tachyarrhythmias**

The principal finding of this study is that 123I-MIBG parameters, especially washout rate is useful for the risk stratification of sudden cardiac death in chronic heart failure patients without SVT. To the best of our knowledge, this is the first report to show a relation between sudden cardiac death and cardiac sympathetic nervous function using 123I-MIBG in heart

Reduced pre-synaptic norepinephrine uptake and post-synaptic beta-adrenoreceptor density might contribute to the remodeling process of the left ventricle in the diseased heart [9]. Increased washout and decreased uptake of 123I-MIBG in the myocardium are related to the severity and prognosis of heart failure [10]. A recent meta-analysis including 18 studies with a total of 1755 patients reconfirmed that decreased uptake and increased washout of 123I-MIBG showed a poor prognosis in patients with heart failure. 123I-MIBG also has been used to assess the functioning of the pulmonary capillary endothelium under a variety of experimental or clinical conditions [11, 12]. Mu et al. speculated the increased lung uptake of 123I-MIBG in heart failure patients might be due to the enhanced permeability of the pulmonary endothelial cells [13]. We have demonstrated that the combined assessment of lung and heart 123I-MIBG uptake may help to predict future clinical outcome in patients with idiopathic dilated cardiomyopathy

We previously investigated the relationship between 123I-MIBG parameters and the anti-beta1 adrenoreceptor autoantibody level in chronic heart failure patients [15]. The autoantibodies stimulate the second extracellular domain of the beta1-adrenoreceptor like norepinephrine, and are associated with reduced cardiac function in patients with heart failure [16]. We have demonstrated that the anti-beta1-adrenoreceptor autoantibodies are closely associated with cardiac sympathetic nervous activity assessed by 123I-MIBG and cardiac event in patients with chronic heart failure [15]. Iwata et al. has reported that the autoantibodies predict VT and sudden death in patients with idiopathic dilated cardiomyopathy [17]. These results suggest that sudden cardiac death associated with ventricular tachyarrhythmias might be related to

Several electrocardiographic markers such as heart rate variability, single-averaged elec‐ trocardiogram, and QT dispersion have been proposed for the prediction of cardiac event in patients with heart failure [18-20]. Heart rate variability is a noninvasive tool for the condition of autonomic nervous activity and has been shown to predict future sudden cardiac death. Tamaki et al. reported a comparison of cardiac 123I-MIBG imaging with other electrocardiographic markers, and concluded that washout rate of 123I-MIBG was There are several limitations in this study. First, because of the retrospective study design, definite conclusions could not be drawn from our present data. BNP which is one of the important prognostic factors should be excluded in our multivariate analysis for prognostic determinants because of imperfect data. Second, the number of cardiac death was relatively small because the follow-up period was not long enough, so that more extensive case studies and longer follow-ups are required to validate the results reported here.
