The Clinical Usefulness of Cardiac Sympathetic Nerve Imaging using 123 Iodine-Meta-iodobenzylguanidine Scintigraphy to Evaluate the Effectiveness of Pharmacological Treatments in Patients with Heart Failure

Abstract The autonomic nervous system plays an important role in the human heart. Activation of the cardiac sympathetic nerve system is a cardinal pathophysiological abnormality associated with the failing human heart. Myocardial imaging using 123 I-metaiodobenzylguanidine（MIBG） , an analogue of norepinephrine, has been applied to investigate the activity of the predominant neurotransmitter of the sympathetic nervous system. 123 I-MIBG uptake in the myocardium is known to be reduced after the onset of heart failure, and improves when heart failure is controlled; therefore, treatments for heart failure may be assessed based on improvements in 123 I-MIBG scintigraphic parameters. In this review, we summarized studies that have focused on the use of cardiac sympathetic nerve imaging using 123 I-MIBG scintigraphy to evaluate the effectiveness of pharmacological treatments in heart failure patients. Keywords: Sympathetic nerve system， 123 I-MIBG scintigraphy，Heart failure Ann Nucl Cardiol 2015；1（1） ：117-126 H eart failure has a ＞20% mortality rate in the first year after its diagnosis and a 5-year mortality rate of approximately 50%（1） . The cardiac sympathetic nervous system and renin-angiotensin-aldosterone-system（RAAS）are crucial compensatory mechanisms during heart failure（2） . Activation of the sympathetic nervous system has been identified as one of the cardinal pathophysiological abnormalities associated with human heart failure（3） . An enhanced sympathetic response is initially favorable because it compensates for decreased cardiac output. However, as heart failure progresses, this response leads to deleterious neurohormonal and myocardial structural changes that worsen the condition and increase the likelihood of arrhythmias and cardiac death（4） . The pharmacological treatment of heart failure involves neurohormonal antagonism, adrenergic blockade, and vasodilators. β-adrenergic blocking agents, such as bisoprolol, metoprolol, and carvedilol, have been shown to improve left ventricular（LV）function and increase the transplant-free survival rate in heart failure patients（5-7） . Angiotensin-converting enzyme（ACE）inhibitors decrease afterload and increase cardiac output, which improves the survival of heart failure patients（8,9） . However, ACE inhibitors do not fully suppress the production of angiotensin II（10） . Therefore, non-ACEmediated enzymatic pathways are important in the conversion of angiotensin I to angiotensin II（11） . Angiotensin II receptor blockers（ARBs）may exert Annals of Nuclear Cardiology Vol. The cellular mechanism of MIBG uptake and storage in pre-synaptic vesicles is identical to that of NE. MIBG and NE share two uptake systems: specific（type-1 or uptake-1）and non-specific（type-2） , using passive diffusion（24） . Type-1 uptake is an active process catalyzed by a temperature-and Na-dependent membrane carrier protein with high affinity and low capacity, which is oxygen-dependent and desipramine-and cocaine-sensitive（25） . Type-2 uptake is temperature-dependent, but Na-and oxygen-independent. In addition, it is nonsaturable up to 5 mM MIBG（24） . At low concentrations, MIBG is primarily taken up via the type-1 mechanism. However, the type-2 mechanism is predominant at high concentrations, for example with 131 I-MIBG. After diffusing through the cell membrane, the tracer is taken up by neurosecretory vesicles via an active transport mechanism（26） . In the scintigraphic method of cardiac sympathetic A and B based on those who did and did not reach a daily dose of ＞20 mg metoprolol by 3 months. The baseline WR in group A was lower than that in group B. After 1 month, the delayed H/M ratio increased in group A, but not in group B. Moreover, de Milliano et al.（30） examined 58 patients with heart failure who were randomized to a maximal tolerable dose of metoprolol or placebo, and found a 21.9% increase in 123 I-MIBG uptake after 6 months, whereas the placebo group showed a 7.8% decrease. The third-generation β-blocker, carvedilol, has been shown to reduce morbidity and mortality in heart failure patients（7） the RAAS in the failing heart than enalapril（50） ; therefore, it may induce a greater improvement in CSNA. Kasama et al.（51）randomly assigned 40 patients with heart failure（LVEF ＜45%）to a perindopril（n＝20）or enalapril（n＝20）group. Six months after the treatment with perindopril, the delayed H/M ratio increased（1.62±0.27 to 1.76±0.29, p＜0.01） and WR decreased（50%±14% to 42%±14%, p＜0.05） . In contrast, no significant differences were observed in patients receiving enalapril. A similar comparative study was conducted by Tsutamoto et al.（52） . Fortyfive heart failure patients undergoing conventional treatments, including enalapril, were randomized into 2 groups; enalapril switched to perindopril group（n＝21） and a continuous enalapril treatment group（n＝24） . In the perindopril group, the delayed H/M ratio significantly increased（2.00±0.07 to 2.15±0.07, p＝0.013）and WR decreased（33.0%±1.4% to 30.5%±1.2%, p＝0.03） after 6 months. Conversely, no significant changes were noted in the enalapril group. These findings（51,52） suggested that perindopril was superior to enalapril and exerted more favorable effects on CSNA, in addition to improved cardiovascular outcomes. 3）Angiotensin II receptor blockers（ARBs） Shinohara et al.（53）published the first study investigating the effects of ARBs on CSNA in heart failure patients. They examined 34 patients with a fractional shortening of the LV diameter ≤25% or LVEF ≤45%, treated with losartan or candesartan. Although no significant difference was observed in the delayed H/M ratio, the WR significantly decreased（32.6%± 7.6% to 28.2%±7.5%; p＜0.001）after 6 months. Thereafter, ARBs were clearly shown to improve CSNA in patients with heart failure when these drugs were administered with ACE inhibitors. Kasama et al. p＜0.001）and WR decreased（47%±9% to 39%±10%; p＜0.01）after 6 months in group A. In contrast, no significant changes were noted in group B. Furthermore, ARBs were suggested to improve the condition of patients with heart failure and preserve LVEF. Kasama et al.（55）selected 50 patients with non-ischemic heart failure and preserved LVEF（＞40%）who were treated with standard treatments. Patients were randomly selected to receive candesartan（n＝25）or placebo（n＝25） . 123 I-MIBG scintigraphic parameters in the candesartan group significantly improved after 6 months, whereas no significant changes were observed in the placebo group. These findings suggested that the addition of candesartan to an ACE inhibitor resulted in the stronger inhibition of RAAS and an increase in the myocardial uptake of NE in heart failure patients with preserved LVEF. The same investigators showed that ARB induced a greater improvement in CSNA than an ACE inhibitor （56） . They examined 50 patients with heart failure （LVEF ＜40%） who were randomly assigned to receive valsartan（n＝25）or enalapril（n＝25） . The delayed H/M ratio increased（1.70±0.17 to 1.78±0.22; p＜ 0.05）and WR decreased（46%±11% to 41%±10%; p＜ 0.05）after a 6-month treatment with valsartan. In contrast, no significant differences were noted after the enalapril treatment. ）Aldosterone blockers（ mineralocorticoid receptor antagonists） Aldosterone has been shown to prevent the uptake of NE in the myocardium（46） ; therefore, several trials were designed to assess improvements in CSNA in patients with heart failure who were being chronically treated with aldosterone receptor blockers. Barr et al. These parameters did not significantly change in group B. These findings were confirmed in a subsequent study by the same investigators（59） . They assessed 30 patients with DCM who were randomly assigned to a spironolactone or conventional treatment, and found that the delayed H/M ratio increased（1.64±0.20 to 1.86±0.27; p＜0.0001）and WR decreased（55%±12% to 41%±15%; p＜0.0005）in the spironolactone only group. Therefore, they concluded that the addition of spironolactone to standard therapy may be more effective for non-ischemic cardiomyopathy than for ischemic cardiomyopathy. were randomly assigned to a candesartan plus spironolactone（group A; n＝25）or to candesartan alone （group B; n＝25）group. After 6 months, all MIBG scintigraphic parameters had improved in both groups. However, the degree of changes in these parameters was significantly better in group A than in group B. 5）Diuretics Loop diuretic treatments activate the RAAS and CSNA and may lead to poor prognoses in heart failure （62） . However, the long-acting loop diuretic, azosemide, has been shown to have a milder effect on the RAAS and CSNA than the short-acting loop diuretic, furosemide （62） . A comparative study of azosemide and furosemide was undertaken by Hisatake et al.（63）and performed using a crossover design: two groups of 11 patients with heart failure were randomized to either azosemide or furosemide. The treatments were administered for 6 months and patients were then transferred over to the second treatment. The delayed H/M ratio（p＝0.011） was significantly higher, while the WR was significantly lower（p＜0.0001）after the final administration in the azosemide group than in the furosemide group. Moreover, torasemide, another loop diuretic, was previously reported to inhibit the RAAS and exhibited anti-aldosteronergic properties in pharmacological stu

The morphology of unipolar potentials predicts the depth of activation foci

Background: The depth of an arrhythmic focus is a major determinant of ablation procedural outcome. This study examined the relationship between the morphology of unipolar potentials and the depth and horizontal distance to activation foci. Methods: Unipolar left ventricular epicardial mapping was performed in 7 open-chest dogs, using silicon sheets with 12 unipolar electrodes 1 mm apart, during bipolar pacing from an octopolar plunge electrode with 1-mm interelectrode spacing. The morphology of the unipolar electrograms was classified as QS, rS, qrS, qRS, rsr’S, or rsR’S. Results: A QS complex was recorded immediately above a subepicardial or mid-myocardial pacing site. An rS complex was recorded away from a subepicardial pacing site. A positive wave originating from a down sloping deflection (R-in-QR) such as r wave in qrS, R wave in qRS, r′ wave in rsr’S or R′ wave in rsR’S complexes was observed when the recording was above a deep myocardial pacing site or away from a mid-myocardial pacing site. The amplitude of negative wave immediately before R-in-QR (Q-in-QR) was inversely correlated with the horizontal (R=−0.40; P<0.0001) and linear (R=−0.22; P=0.0006) distance to the pacing site, and the amplitude of R-in-QR was positively correlated with the horizontal (R=0.25; P=0.0001) and linear (R=0.29; P<0.0001) distance to the pacing site. The amplitude of the initial r wave was not correlated with the depth or horizontal and linear distance to the pacing site. Conclusion: The morphology of unipolar electrograms predicted the horizontal distance and the depth of nearby foci of activation

Left intraventricular dyssynchrony caused by a false tendon

Left ventricular (LV) false tendons are usually benign, intraventricular myocardial structures, which may cause functional malfunction or deformation of the LV cavity due to mechanical stretching and dilatation of the LV wall. We present a case of non-ischemic cardiomyopathy complicated with intraventricular dyssynchrony that was caused by complete left bundle branch block and the mechanical pressure exerted by the stiff false tendon on the weakened mid-septum during systole

Measurement of the ventriculoatrial interval from the coronary sinus during para-Hisian pacing may fail to distinguish ventriculoatrial nodal conduction from conduction over a septal accessory pathway

Background: Para-Hisian pacing (PHP) helps differentiate retrograde conduction over an accessory pathway (AP) from retrograde conduction over the atrioventricular (AV) node. This study examined a potential limitation of this technique, focusing on the measurement of the ventriculoatrial (V–A) interval from the coronary sinus (CS) during PHP. Methods: Our subjects were 9 patients undergoing electrophysiological studies before successful catheter ablation of a posteroseptal AP. During PHP, retrograde conduction occurred over an AP when the pacing stimulus to atrium (S–A) interval recorded near the AP remained unchanged whether the His bundle (HB) was captured or not (pattern 1), or when a loss of HB capture was associated with an increase in the S–A interval and no change in the V–A interval near the AP (pattern 2). Results: Patterns 1 and 2 were observed in 5 (56%) and 2 (22%) patients, respectively. However, in the remaining 2 patients (22%), loss of HB capture during PHP was associated with an increase in the S–A interval (as in pattern 2), whereas the V–A interval near the AP could not be measured because no ventricular electrogram was visible on the CS recording (pattern 3); therefore, the presence of AP could not be confirmed by PHP. In patterns 2 and 3, the atrial activation sequence remained unchanged whether the HB was captured or not. Conclusions: PHP may not be able to discriminate between a retrograde septal AP and AV nodal conduction in patients whose proximal CS recording shows no visible ventricular electrogram