**2. Methods**

### **2.1. Patients**

We retrospectively examined 120 consecutive heart failure patients with a left ventricular ejection fraction (LVEF) of less than 50 % who underwent 123I-MIBG scintigraphy between April 1998 and December 2004. There were 84 men and 36 women with a mean age of 57±14 years ranging from 22 to 95 years. New York Heart Association (NYHA) functional class assessment at the time of the scintigraphy showed 23 patients in class I, 66 in class II and 31 in class III. All patients underwent cross sectional and M-mode echocardiography as well as coronary angiography. The study population included non-ischemic dilated cardiomyopathy in 73 patients, ischemic cardiomyopathy in 21 and others in 26 which systolic dysfunction might be caused by valvular diseases, hypertension and/or congenital heart disease. All patients showed stable clinical condition for at least 3 months on conventional medications with angiotensin-converting enzyme inhibitor and diuretics. Fifty-nine patients were on β– blocker drugs.

#### **2.2. 123I-MIBG data acquisition**

123I-MIBG is an analogue of guanethidine that is metabolized in a qualitatively similar manner to norepinephrine at the synaptic nerve terminal. After 123I-MIBG uptakes through the uptake-1 mechanism and storages in the synaptic nerve ending, it releases according to the sympathetic activity. Since the myocardium of patients with chronic heart failure is characterized by a significant reduction of pre-synaptic norepinephrine uptake and post-synaptic beta-adrenor‐ eceptor density, uptake-1 function and beta–receptor downregulation can be evaluated by 123I-MIBG imaging [8]. Under resting and fasting condition, patients were injected intrave‐ nously with 111MBq of commercially available 123I-MIBG (Daiichi Radioisotopes Labs, Tokyo, Japan). Anterior planar images were acquired 15 minutes and 3 hours after the injection and stored in a 64 x 64 matrix by means of a scintillation camera (model ZLC 7500; Siemens, Solana, Sweden) equipped with a long-energy, general purpose collimator interfaced to a minicom‐ puter (SCINTIPAC 7000; Shimazu, Kyoto, Japan), with a 20% window centered on the 159keV photopeak of Iodine-123. Regions of interest (ROI) were manually drawn over the heart and upper mediastinum by a nuclear cardiologist without knowledge of the patient's data (Figure 1). The total number of counts of each ROI was determined, and a geometric mean was calculated as counts per pixel. We determined the heart to mediastinum activity ratio (H/M) for all early and delayed images. 123I-MIBG washout rate from the heart was calculated from the difference between early and delayed images according to the formula shown in figure 1.

Demonstrable two cases are shown in figure 1. A case with NYHA class III shows lower H/M ratio and higher washout rate as compared to a case with NYHA class I.

cardiac death. Sudden cardiac death was defined as death within 1 hour after the acute onset of symptom, death during sleep or unwitnessed death. Clinical course of the 120 patients are summarized in figure 2. During a mean follow-up of 57±24 months, 14 patients died of refractory heart failure and 11 died suddenly including 9 without clinical VT. Echocardia‐ graphic and hemodynamic variables ware compared among the three groups. Plasma norepinephrin concentration of 40 patients and brain natriuretic polypeptide (BNP) of 64

H: heart; M:mediastinum; H/M: heart to mediastinum activity ratio; 123I-MIBG: Iodine-123 Metaiodobenzylguanidine;

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231

**Figure 1.** 123I-MIBG imaging. (A) A case of NYHA functional class I status. (B) A case of NYHA functional class III status.

NYHA: New York Heart Association.

VT: ventricular tachycardia

**Figure 2.** Clinical course of all patients.

patients were measured close to the time of scintigraphic examination.

#### **2.3. Follow-up information and end-point**

Medical records of all patients were carefully reviewed. The primary end-point of this study was the occurrence of cardiac death including death due to congestive heart failure and sudden Risk Stratification of Sudden Cardiac Death by Evaluating Myocardial Sympathetic Nerve Activity Using Iodine-123… http://dx.doi.org/10.5772/55615 231

H: heart; M:mediastinum; H/M: heart to mediastinum activity ratio; 123I-MIBG: Iodine-123 Metaiodobenzylguanidine; NYHA: New York Heart Association.

**Figure 1.** 123I-MIBG imaging. (A) A case of NYHA functional class I status. (B) A case of NYHA functional class III status.

VT: ventricular tachycardia

**2. Methods**

230 Cardiomyopathies

**2.1. Patients**

blocker drugs.

**2.2. 123I-MIBG data acquisition**

We retrospectively examined 120 consecutive heart failure patients with a left ventricular ejection fraction (LVEF) of less than 50 % who underwent 123I-MIBG scintigraphy between April 1998 and December 2004. There were 84 men and 36 women with a mean age of 57±14 years ranging from 22 to 95 years. New York Heart Association (NYHA) functional class assessment at the time of the scintigraphy showed 23 patients in class I, 66 in class II and 31 in class III. All patients underwent cross sectional and M-mode echocardiography as well as coronary angiography. The study population included non-ischemic dilated cardiomyopathy in 73 patients, ischemic cardiomyopathy in 21 and others in 26 which systolic dysfunction might be caused by valvular diseases, hypertension and/or congenital heart disease. All patients showed stable clinical condition for at least 3 months on conventional medications with angiotensin-converting enzyme inhibitor and diuretics. Fifty-nine patients were on β–

123I-MIBG is an analogue of guanethidine that is metabolized in a qualitatively similar manner to norepinephrine at the synaptic nerve terminal. After 123I-MIBG uptakes through the uptake-1 mechanism and storages in the synaptic nerve ending, it releases according to the sympathetic activity. Since the myocardium of patients with chronic heart failure is characterized by a significant reduction of pre-synaptic norepinephrine uptake and post-synaptic beta-adrenor‐ eceptor density, uptake-1 function and beta–receptor downregulation can be evaluated by 123I-MIBG imaging [8]. Under resting and fasting condition, patients were injected intrave‐ nously with 111MBq of commercially available 123I-MIBG (Daiichi Radioisotopes Labs, Tokyo, Japan). Anterior planar images were acquired 15 minutes and 3 hours after the injection and stored in a 64 x 64 matrix by means of a scintillation camera (model ZLC 7500; Siemens, Solana, Sweden) equipped with a long-energy, general purpose collimator interfaced to a minicom‐ puter (SCINTIPAC 7000; Shimazu, Kyoto, Japan), with a 20% window centered on the 159keV photopeak of Iodine-123. Regions of interest (ROI) were manually drawn over the heart and upper mediastinum by a nuclear cardiologist without knowledge of the patient's data (Figure 1). The total number of counts of each ROI was determined, and a geometric mean was calculated as counts per pixel. We determined the heart to mediastinum activity ratio (H/M) for all early and delayed images. 123I-MIBG washout rate from the heart was calculated from the difference between early and delayed images according to the formula shown in figure 1.

Demonstrable two cases are shown in figure 1. A case with NYHA class III shows lower H/M

Medical records of all patients were carefully reviewed. The primary end-point of this study was the occurrence of cardiac death including death due to congestive heart failure and sudden

ratio and higher washout rate as compared to a case with NYHA class I.

**2.3. Follow-up information and end-point**

**Figure 2.** Clinical course of all patients.

cardiac death. Sudden cardiac death was defined as death within 1 hour after the acute onset of symptom, death during sleep or unwitnessed death. Clinical course of the 120 patients are summarized in figure 2. During a mean follow-up of 57±24 months, 14 patients died of refractory heart failure and 11 died suddenly including 9 without clinical VT. Echocardia‐ graphic and hemodynamic variables ware compared among the three groups. Plasma norepinephrin concentration of 40 patients and brain natriuretic polypeptide (BNP) of 64 patients were measured close to the time of scintigraphic examination.

#### **2.4. Statistical analysis**

Student's *t*-test was used to compare all continuous variables expressed as mean ± SD of the two groups. Incidence was compared by means of χ<sup>2</sup> tests. Receiver operating characteristic analysis was used to select the most appropriate indicator of 123I-MIBG. Survival rates were estimated with the Kaplan-Meier method, and differences in survival assessed with the logrank test. Univariate and multivariate analyses of the event risks associated with selected clinical variables used the Cox proportional hazard model (SPSS v 9.0, Chicago, IL). A *p* value of < 0.05 was considered statistically significant.

### **3. Results**

#### **3.1. Comparisons of clinical variables among patients stratified by cause of death (table 1)**

Patients who died of congestive heart failure were significantly older than those who survived, or died suddenly without SVT. The patients with congestive heart failure death also showed the most deteriorated echocardiographic and hemodynamic conditions among the 3 groups. There were no statistically significant differences in any variables between surviving patients and patients who died suddenly without SVT.

**3.2. Comparisons of 123I-MIBG parameters among patients stratified by cause of death**

died suddenly, although clinical variables were similar between the two groups.

**3.4. Univariate predictors for heart failure death and sudden death**

123I-MIBG parameters were better in surviving patients compared to those in patients with death due to congestive heart failure and with sudden death. There were significant differences in delayed H/M and washout rate of 123I-MIBG between surviving patients and patients who

CHF: congestive heart failure; H/M: heart to mediastinum activity ratio; 123I-MIBG: Iodine-123 Metaiodobenzylguani‐

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233

**Figure 3.** Comparisons of delayed H/M (left panel) and washout rate (right panel) of 123I-MIBG among the patients

Comparison of Kaplan-Meier survival curve was depicted in figure 4. Receiver operating characteristic analysis indicated that the optimal cut-off point of the delayed heart to media‐ stinum ratio for all cause of cardiac death was 1.6. Survival of the patients with delayed H/M ratio greater than 1.6 was significantly worse than that less than 1.6. Receiver operating characteristic analysis indicated that the optimal cut-off point of heart 123I-MIBG washout rate for all cause of cardiac death was 38%. Survival of the patients with washout rate greater than 38% was significantly worse than that less than 38%. In the analysis of washout rate, a log-rank statistics of sudden cardiac death in heart failure patients without SVT was greater than that of death due to heart failure, whereas similar in the analysis of the delayed H/M ratio.

Univariate predictors for heart failure death are summarized in Table 2. Age, left ventricular end-diastolic diameter, left ventricular ejection fraction (LVEF), pulmonary capillary wedge pressure, mean pulmonary artery pressure, delayed H/M ratio, and heart 123I-MIBG washout

**(figure 3)**

stratified by cause of death

dine

**3.3. Survival**


\* p < 0.05 (for sudden death and survived patients); † p <0.05 (for survived patients)

BNP:brain natreuretic peptide; CI:cardiac index; LVDd:left ventricular end-diastolic diameter; LVEF: left

ventricular ejection fraction; PCWP:pulmonary capillary wedge pressure; mPAP:mean pulmonary wedge pressure

**Table 1.** Clinical Variables among the Patients Stratified by Cause of Death

Risk Stratification of Sudden Cardiac Death by Evaluating Myocardial Sympathetic Nerve Activity Using Iodine-123… http://dx.doi.org/10.5772/55615 233

CHF: congestive heart failure; H/M: heart to mediastinum activity ratio; 123I-MIBG: Iodine-123 Metaiodobenzylguani‐ dine

**Figure 3.** Comparisons of delayed H/M (left panel) and washout rate (right panel) of 123I-MIBG among the patients stratified by cause of death

#### **3.2. Comparisons of 123I-MIBG parameters among patients stratified by cause of death (figure 3)**

123I-MIBG parameters were better in surviving patients compared to those in patients with death due to congestive heart failure and with sudden death. There were significant differences in delayed H/M and washout rate of 123I-MIBG between surviving patients and patients who died suddenly, although clinical variables were similar between the two groups.

#### **3.3. Survival**

**2.4. Statistical analysis**

232 Cardiomyopathies

**3. Results**

two groups. Incidence was compared by means of χ<sup>2</sup>

of < 0.05 was considered statistically significant.

and patients who died suddenly without SVT.

Student's *t*-test was used to compare all continuous variables expressed as mean ± SD of the

analysis was used to select the most appropriate indicator of 123I-MIBG. Survival rates were estimated with the Kaplan-Meier method, and differences in survival assessed with the logrank test. Univariate and multivariate analyses of the event risks associated with selected clinical variables used the Cox proportional hazard model (SPSS v 9.0, Chicago, IL). A *p* value

**3.1. Comparisons of clinical variables among patients stratified by cause of death (table 1)**

Patients who died of congestive heart failure were significantly older than those who survived, or died suddenly without SVT. The patients with congestive heart failure death also showed the most deteriorated echocardiographic and hemodynamic conditions among the 3 groups. There were no statistically significant differences in any variables between surviving patients

> **Sudden death without s-VTCHF Survived (N=9) (N=14) (N=95)**

Age (yrs.) 56.0±5.8 64.0±8.5\* 55.3±14.2 Gender: Female 1 (10) 3 (21) 32(33) β-blockers 4 (40) 5 (36) 59(63) LVEDd (mm) 62.5±15.0 67.6±12.1† 62.8±9.8 LVEF (%) 30.8±11.2 22.6±10.3† 36.1±13.2 PCWP (mmHg) 13.1±6.3 21.0±8.7\* 11.0±6.1 mPAP (mmHg) 22.8±7.4 30.9±9.0\* 18.5±7.2 CI (l/min/mm2) 2.51±0.73 2.21±0.47 2.61±1.25 **BNP** (pg/ml) **219±255 697±516† 107±110**

\* p < 0.05 (for sudden death and survived patients); † p <0.05 (for survived patients)

**Table 1.** Clinical Variables among the Patients Stratified by Cause of Death

BNP:brain natreuretic peptide; CI:cardiac index; LVDd:left ventricular end-diastolic diameter; LVEF: left

ventricular ejection fraction; PCWP:pulmonary capillary wedge pressure; mPAP:mean pulmonary wedge pressure

tests. Receiver operating characteristic

Comparison of Kaplan-Meier survival curve was depicted in figure 4. Receiver operating characteristic analysis indicated that the optimal cut-off point of the delayed heart to media‐ stinum ratio for all cause of cardiac death was 1.6. Survival of the patients with delayed H/M ratio greater than 1.6 was significantly worse than that less than 1.6. Receiver operating characteristic analysis indicated that the optimal cut-off point of heart 123I-MIBG washout rate for all cause of cardiac death was 38%. Survival of the patients with washout rate greater than 38% was significantly worse than that less than 38%. In the analysis of washout rate, a log-rank statistics of sudden cardiac death in heart failure patients without SVT was greater than that of death due to heart failure, whereas similar in the analysis of the delayed H/M ratio.

#### **3.4. Univariate predictors for heart failure death and sudden death**

Univariate predictors for heart failure death are summarized in Table 2. Age, left ventricular end-diastolic diameter, left ventricular ejection fraction (LVEF), pulmonary capillary wedge pressure, mean pulmonary artery pressure, delayed H/M ratio, and heart 123I-MIBG washout

**X2 HR 95%CI** *p value*

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235

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

CI:cardiac index; H/M:heart to mediastinum activity ratio; LVDd:left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; PCWP:pulmonary capillary wedge pressure; mPAP:mean pulmonary wedge pressure;

Cox multiple variable logistic regression model with a backward stepwise approach including 10 clinical variables (age, gender, on beta-blockers, left ventricular end-diastolic diameter, pulmonary capillary wedge pressure, mean pulmonary artery pressure, cardiac index, LVEF, delayed H/M ratio, heart 123I-MIBG washout rate) identified pulmonary capillary wedge pressure and delayed H/M ratio as independent predictors of death due to heart failure, and delayed H/M ratio and heart 123I-MIBG washout rate as independent predictors of sudden

X2 HR 95%CI *p* value

**(a) For Heart Failure Death** X2 HR 95%CI *p* value

**(b) For Sudden Death without Sustained VT** (a) Hazard ratio (HR) reflects risk with an increase of 1\*. H/M:heart to mediastinum activity ratio; PCWP:pulmonary

(b) Hazard ratio (HR) reflects risk with an increase of 1\*. H/M:heart to mediastinum activity ratio; VT: ventricular

PCWP\* 15.3 1.28 1.078–1.409 .0000 Delayed H/M\* 6.25 0.01 0.001–0.124 .012

Washout rate\* 5.12 1.05 1.007–1.126 .024 Delayed H/M\* 4.29 0.02 0.023–0.346 038

Age (yrs.)\* 0.27 0.99 0.953–1.028 .605 Gender :Male 2.96 0.17 0.022–1.282 .085 on β-blockade 1.71 0.47 0.154–1.452 .191 LVDd (mm)\* 0.41 1.02 0.965–1.073 .521 PCWP (mmHg)\* 0.18 1.02 0.937–1.107 .671 mPAP (mmHg)\* 0.87 1.03 0.966–1.104 .350 CI (l/min/mm2)† 0.02 0.94 0.425–2.086 .881 LVEF (%)\* 1.00 0.98 0.934–1.023 .318 Delayed H/M\* 12.8 0.01 0.001–0.116 .0004 Washout rate (%)\* 14.8 1.06 1.027–1.086 .0001

Hazard ratio reflects risk with an increase of 1\* and 0.1†.

**Table 3.** Univariate Predictors for Sudden Death without Sustained VT

cardiac death in heart failure patients without SVT (Table 4).

VT:ventricular tachycardia

capillary wedge pressure

**Table 4.** Multiivariate analysis

tachycardia

**3.5. Multivariate analysis**

H/M: heart to mediastinum activity ratio; 123I-MIBG: Iodine-123 Metaiodobenzylguanidine; VT: ventricular tachycar‐ dia

**Figure 4.** Comparison of Kaplan-Meier survival curves. Heart failure death (left panel) abd sudden cardiac death (right panel).

rate were associated with death due to heart failure. Univariate predictors for sudden cardiac death are summarized in Table 3. Delayed H/M ratio and heart 123I-MIBG washout rate were associated with sudden cardiac death in heart failure patients without SVT.


Hazard ratio reflects risk with an increase of 1\* and 0.1†.

CI:cardiac index; H/M:heart to mediastinum activity ratio; LVDd:left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; PCWP:pulmonary capillary wedge pressure; mPAP:mean pulmonary wedge pressure

**Table 2.** Univariate Predictors for Heart Failure Death

Risk Stratification of Sudden Cardiac Death by Evaluating Myocardial Sympathetic Nerve Activity Using Iodine-123… http://dx.doi.org/10.5772/55615 235


Hazard ratio reflects risk with an increase of 1\* and 0.1†.

CI:cardiac index; H/M:heart to mediastinum activity ratio; LVDd:left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; PCWP:pulmonary capillary wedge pressure; mPAP:mean pulmonary wedge pressure; VT:ventricular tachycardia

**Table 3.** Univariate Predictors for Sudden Death without Sustained VT

#### **3.5. Multivariate analysis**

rate were associated with death due to heart failure. Univariate predictors for sudden cardiac death are summarized in Table 3. Delayed H/M ratio and heart 123I-MIBG washout rate were

H/M: heart to mediastinum activity ratio; 123I-MIBG: Iodine-123 Metaiodobenzylguanidine; VT: ventricular tachycar‐

**Figure 4.** Comparison of Kaplan-Meier survival curves. Heart failure death (left panel) abd sudden cardiac death (right

**X2 HR 95%CI** *p value*

associated with sudden cardiac death in heart failure patients without SVT.

Age (yrs.)\* 4.39 1.07 1.004–1.141 .036 Gender :Male 0.72 0.57 0.153–2.104 .397 on β-blockade 2.25 0.40 0.119–1.327 .134 LVDd (mm)\* 2.31 1.04 0.988–1.105 .129 PCWP (mmHg)\* 21.3 1.24 1.131–1.357 .0000 mPAP (mmHg)\* 20.8 1.19 1.105–1.283 .0000 CI (l/min/mm2)† 5.17 0.19 0.045–0.795 .023 LVEF (%)\* 8.90 0.91 0.861–0.969 .003 Delayed H/M\* 11.9 0.01 0.001–0.124 .0006 Washout rate (%)\* 2.17 1.03 0.991–1.064 .141

CI:cardiac index; H/M:heart to mediastinum activity ratio; LVDd:left ventricular end-diastolic diameter; LVEF:

left ventricular ejection fraction; PCWP:pulmonary capillary wedge pressure; mPAP:mean pulmonary wedge pressure

Hazard ratio reflects risk with an increase of 1\* and 0.1†.

dia

panel).

234 Cardiomyopathies

**Table 2.** Univariate Predictors for Heart Failure Death

Cox multiple variable logistic regression model with a backward stepwise approach including 10 clinical variables (age, gender, on beta-blockers, left ventricular end-diastolic diameter, pulmonary capillary wedge pressure, mean pulmonary artery pressure, cardiac index, LVEF, delayed H/M ratio, heart 123I-MIBG washout rate) identified pulmonary capillary wedge pressure and delayed H/M ratio as independent predictors of death due to heart failure, and delayed H/M ratio and heart 123I-MIBG washout rate as independent predictors of sudden cardiac death in heart failure patients without SVT (Table 4).


(a) Hazard ratio (HR) reflects risk with an increase of 1\*. H/M:heart to mediastinum activity ratio; PCWP:pulmonary capillary wedge pressure

(b) Hazard ratio (HR) reflects risk with an increase of 1\*. H/M:heart to mediastinum activity ratio; VT: ventricular tachycardia

**Table 4.** Multiivariate analysis
