Takeru Wakabayashi

Cardiac death prediction and impaired cardiac sympathetic innervation assessed by MIBG in patients with failing and nonfailing hearts.

BackgroundAlthough cardiac sympathetic nerve dysfunction is related to poor clinical outcome, a critical sympathetic dysfunction level for predicting cardiac death is still unclear. The current study was designed to investigate which indices derived from metaiodobenzylguanidine (MIBG) imaging have prognostic value compared with clinical and cardiac function variables, and to determine the threshold of cardiac MIBG activity for identifying patients likely to suffer cardiac death in both failing and nonfailing hearts.Methods and ResultsMyocardial I-123-MIBG activity was quantified as a heart-to-mediastinum ratio in 414 consecutive patients, 173 (42%) of whom had symptomatic heart failure. After cardiac function measurements, patients were followed up with an end-point of cardiac or noncardiac death. During a mean follow-up period of 22 months, 37 cardiac deaths occurred: 23 resulted from heart failure, 9 were sudden cardiac deaths, and 5 were fatal myocardial infarctions. Multivariate analysis using the Wald χ2 and the Cox proportional hazard model revealed that late heart-to-mediastinum ratio, the use of nitrates, early heart-to-mediastinum ratio, and left ventricular ejection fraction were independent predictors of cardiac death; late heart-to-mediastinum ratio, New York Heart Association (NYHA) class, the presence of previousmyocardial infarction, and age were independent predictors of heart failure and sudden cardiac death. Late heart-to-mediastinum ratio was the most powerful predictor of overall cardiac death among the variables. The Kaplan-Meier analysis showed that a late heart-to-mediastinum ratio of 1.74 or less, age greater than 60 years, the presence of myocardial infarction, and NYHA functional class 3 or 4 strongly indicated poor clinical outcomes. Furthermore, the more powerful incremental prognostic values were obtained by using MIBG imaging in combination with conventional clinical variables.ConclusionsImpaired cardiac sympathetic innervation assessed by MIBG activity has the greatest potential for predicting cardiac death and may be useful for identifying a threshold level for selecting patients at risk for death by heart failure, sudden cardiac death, and fatal myocardial infarction.

Predicting the Need for an Implantable Cardioverter Defibrillator Using Cardiac Metaiodobenzylguanidine Activity Together with Plasma Natriuretic Peptide Concentration or Left Ventricular Function

Despite widespread use of implantable cardioverter defibrillators (ICDs), their cost and the fact that only a certain group of patients fully benefits from the devices require appropriate risk stratification of patients. This study investigated whether altered cardiac autonomic function is associated with the occurrence of ICD discharge or lethal cardiac events. Methods: Fifty-four ICD-treated patients were prospectively followed after assessment of cardiac metaiodobenzylguanidine (MIBG) activity, quantified as the heart-to-mediastinum ratio (HMR), plasma concentration of brain natriuretic peptide (BNP), and left ventricular ejection fraction (LVEF). Patients were divided into 2 groups based on the presence (group A, n = 21) or absence (group B, n = 33) of appropriate ICD discharge during a 15-mo period. Results: Group A had a significantly lower level of MIBG activity and a higher plasma BNP level than did group B. Univariate analysis revealed BNP level, any medication, and late HMR to be significant predictors, and multivariate analysis showed late HMR to be an independent predictor. An HMR of less than 1.95 with a plasma BNP level of more than 187 pg/mL or an LVEF of less than 50% had significantly increased power to predict ICD shock: positive predictive values, 82% (HMR + BNP) and 58% (HMR + LVEF); negative predictive values, 73% (HMR + BNP) and 77% (HMR + LVEF); sensitivities, 45% (HMR + BNP) and 67% (HMR + LVEF); and specificities, 94% (HMR + BNP) and 70% (HMR + LVEF). Conclusion: When combined with plasma BNP concentration or cardiac function, cardiac MIBG activity is closely related to lethal cardiac events and can be used to identify patients who would benefit most from an ICD.

Clinical implications of midventricular obstruction and intravenous propranolol use in transient left ventricular apical ballooning (Tako-tsubo cardiomyopathy)

BACKGROUND Persistent hypotension with dynamic midventricular obstruction (MVO) in patients with transient left ventricular (LV) apical ballooning (Tako-tsubo cardiomyopathy) is an important complication that needs to be treated. PURPOSE The objective of this study is to determine the effects of intravenous propranolol challenge on MVO in transient LV apical ballooning. SUBJECTS AND METHODS Thirty-four patients (12 males, 22 females, mean age 64 +/- 17 years, age range 22-84 years) with LV apical ballooning were enrolled. The hemodynamic and echocardiographic effects of propranolol (0.05 mg/kg, maximum 4 mg) were analyzed in 13 patients. RESULTS (1) Midventricular obstruction was present in 8 (24%) of 34 patients, and the pressure gradient (PG) ranged from 28 to 140 mm Hg. (2) Patients with MVO had similar demographic and clinical characteristics (symptoms, peak creatine kinase, plasma catecholamine levels) as those without MVO; however, in patients with MVO, abnormal Q waves on electrocardiogram and hypotension were more prevalent. (3) In the MVO group, intravenous propranolol changed the PG from 90 +/- 42 to 22 +/- 9 mm Hg, the systolic blood pressure (SBP) from 85 +/- 11 to 116 +/- 20 mm Hg, and the LV ejection fraction (LVEF) from 30% +/- 7% to 43% +/- 4%. (4) In all subjects, the changes in the PG after propranolol injection had a significant linear correlation with the SBP and LVEF changes: deltaSBP = 4.738 + 0.315 x deltaPG (r = 0.689 (P < .001) and deltaLVEF = 2.973 + 0.1321 x deltaPG (r = 0.715, P < .001). CONCLUSION Intravenous propranolol is useful for treating dynamic MVO in patients with transient LV apical ballooning.

Cardiac metaiodobenzylguanidine activity can predict the long-term efficacy of angiotensin-converting enzyme inhibitors and/or beta-adrenoceptor blockers in patients with heart failure

PurposeAlthough the benefits of treatment with angiotensin-converting enzyme (ACE) inhibitors and beta-blockers are well known, no method has as yet been established to predict the efficacy of drug therapy. This study tested whether cardiac 123I-metaiodobenzylguanidine (MIBG) activity is of prognostic value and can predict the improvement in heart failure patients resulting from treatment with ACE inhibitors and/or beta-blockers.MethodsFollowing quantification of the heart-to-mediastinum ratio (HMR) of MIBG activity, 88 patients with heart failure who were treated with ACE inhibitors and/or beta-blockers (treated group) and 79 patients with heart failure who were treated conventionally without the aforementioned agents, and who served as controls, were followed up for 43 months with a primary endpoint of cardiac death.ResultsThe treated group had a significantly lower prevalence of cardiac death and a significantly lower mortality at 5 years compared with the control group (15% vs 37% and 21% vs 42%, p<0.05, respectively). Multivariate analysis revealed that significant predictors were HMR, age, nitrate use and ventricular tachycardia for the treated group, and HMR, nitrate use and NYHA class for the control group. The drug treatment significantly reduced mortality from 36% to 12% when HMR was 1.53 or more and from 53% to 37% when HMR was less than 1.53. The reduction in risk of mortality within 5 years in patients without a severe MIBG defect (67%) was twice that in patients with such a defect (32%) (p<0.05).ConclusionThe reduction in mortality risk achieved by using ACE inhibitors and/or beta-blockers is associated with the severity of impairment of cardiac MIBG uptake. Cardiac MIBG activity can consequently be of long-term prognostic value in predicting the effectiveness of such treatment in patients with heart failure.

Prediction of New-Onset Refractory Congestive Heart Failure Using Gated Myocardial Perfusion SPECT Imaging in Patients With Known or Suspected Coronary Artery Disease : Subanalysis of the J-ACCESS Database

OBJECTIVES The purpose of this study was to evaluate the predictive value of perfusion/function parameters measured by gated myocardial perfusion single-photon emission computed tomography (SPECT)in combination with clinical variables in patients with known or suspected coronary artery disease to predict refractory heart failure (HF). BACKGROUND The increasing number of HF patients requires the establishment of a prophylactic strategy that can identify patients at high risk of HF due to coronary artery disease. METHODS We analyzed clinical and stress/rest-gated SPECT data from the multicenter, prospective, and observational J-ACCESS (Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT) database of 3,835 known or suspected coronary artery disease patients in which new-onset congestive HF symptoms requiring aggressive medical treatment were observed in 71 patients for 3 years. RESULTS The multivariable Cox hazard model revealed that chronic renal dysfunction (hazard ratio(HR): 6.227 [95% confidence interval (CI): 2.920 to 13.279]), the end-systolic volume index (ESVI) (HR:1.019 [95% CI: 1.011 to 1.029]), and moderate to high stress summed score (SSS) (HR: 3.012 [95% CI: 1.757 to 5.181]) independently (p < 0.0001) predicted HF. In addition to the close (p < 0.0001) correlation of ESVI and SSS with HF incidence, the combined tertiles of SSS and ESVI revealed high-risk patients with a maximally 17.3 times greater risk (5.2%/3 years) compared with the minimal risk (0.3%/3 years) at a normal to low SSS and lower ESVI. Chronic renal dysfunction combined with ESVI and SSS categories had the greatest (p < 0.005 to 0.001) incremental prognostic value with a global chi-square value (125.0)over single or other combined risks. CONCLUSIONS Chronic renal dysfunction, greater stress-induced perfusion abnormality, and higher ESVI provide independent and additive information for predicting the risk of refractory HF in known or suspected coronary patients, indicating the efficacy of perfusion/function parameters measured by stress gated perfusion SPECT for identifying patients at greater risk of future refractory HF.

Cardiac Mortality Assessment Improved by Evaluation of Cardiac Sympathetic Nerve Activity in Combination with Hemoglobin and Kidney Function in Chronic Heart Failure Patients

We examined prognostic interactions among cardiac autonomic function assessed by 123I-labeled metaiodobenzylguanidine (123I-MIBG) activity, hemoglobin, and kidney function in chronic heart failure patients. Anemia, chronic kidney disease, and impairment of cardiac sympathetic function have been shown as determinants of prognosis in heart failure patients, but there has been little information on their synergistic correlations with cardiac mortality. Methods: After evaluations of hemoglobin and estimated glomerular filtration rate (GFR), 468 heart failure patients with left ventricular ejection fraction less than 50% underwent cardiac 123I-MIBG imaging before discharge and were then followed up for a mean interval of 60.5 mo with a primary endpoint of cardiac death. Cardiac 123I-MIBG activity was quantified using heart-to-mediastinum ratio (HMR) and washout rate. Results: For 89 fatal cardiac events documented (19.0%), besides New York Heart Association class, multivariate Cox analysis revealed HMR, hemoglobin, and estimated GFR as significant independent determinants, with hazard ratios of 0.215 (P = 0.0129; 95% confidence interval [CI], 0.064–0.718), 0.821 (P = 0.0062; 95% CI, 0.708–0.946), and 0.984 (P = 0.0243; 95% CI, 0.970–0.998), respectively. Receiver-operating-characteristic analysis determined the thresholds for identifying patients at increased risk for cardiac death to be 1.57 for HMR, 11.9 g/dL for hemoglobin, and 46.4 mL/min/1.73 m2 for estimated GFR. Combining the 4 independent predictors incrementally (P < 0.05) improved prognostic powers maximally up to a global χ2 value of 97.3 compared with sole or other combinations. Conclusion: Hemoglobin, kidney function, and alterations of cardiac sympathetic nerve activity are independently and synergistically associated with increased cardiac mortality in chronic heart failure patients, together with New York Heart Association functional class.

Synergistic prognostic values of cardiac sympathetic innervation with left ventricular hypertrophy and left atrial size in heart failure patients without reduced left ventricular ejection fraction: a cohort study

Objectives This study tested whether cardiac sympathetic innervation assessed by metaiodobenzylguanidine (MIBG) activity has long-term prognostic value in combination with left ventricular hypertrophy (LVH) and left atrial size in heart failure (HF) patients without reduced left ventricular ejection fraction (LVEF). Design A single-centre prospective cohort study. Setting/participants With primary endpoints of cardiac death and rehospitalisation due to HF progression, 178 consecutive symptomatic HF patients with 74% men, mean age of 56 years and mean LVEF of 64.5% were followed up for 80 months. The entry criteria consisted of LVEF more than 50%, completion of predischarge clinical evaluations including cardiac MIBG and echocardiographic studies and at least more than 1-year follow-up when survived. Results Thirty-four patients with cardiac evens had larger left atrial dimension (LAD), increased LV mass index, reduced MIBG activity quantified as heart-to-mediastinum ratio (HMR) than did the others. Multivariable Cox analysis showed that LAD and HMR were significant predictors (HR of 1.080 (95% CI 1.00 to 1.16, p=0.044) and 0.107 (95% CI 0.01 to 0.61, p=0.012, respectively). Thresholds of HMR (1.65) and LAD (37 mm) were closely related to identification of high-risk patients. In particular, HMR was a significant determinant of cardiac events in both patients with and without LV hypertrophy. Reduced HMR with enlarged LAD or LV hypertrophy identified patients at most increased risk; overall log-rank value, 11.5, p=0.0032 for LAD and 17.5, p=0.0002, respectively. Conclusions In HF patients without reduced LV ejection fraction, impairment of cardiac sympathetic innervation is related to cardiac outcomes independently and synergistically with LA size and LV hypertrophy. Cardiac sympathetic innervation assessment can contribute to better risk-stratification in combination with evaluation of LA size and LV mass but is needed to be evaluated for establishing aetiology-based risk assessment in HF patients at increased risk.

Assessment of Cardiac Sympathetic Innervation in Heart Failure and Lethal Arrhythmias: Therapeutic and Prognostic Implications

Sympathetic nerve activities have pivotal roles in pathophysiology and prognosis in patients with heart failure. Among the various available techniques for the analysis of sympathetic nerve function, cardiac neuroimaging with a norepinephrine analogue is a noninvasive, specific and powerful modality that enables in vivo assessment of cardiac sympathetic innervation and activity and has demonstrated pathophysiological alterations at pre-synaptic nerve terminals and their clinical implications. Impaired cardiac metaiodobenzylguanidine (MIBG) activity and, conversely, increased systemic sympathetic function drive closely correlate with clinical outcomes. Cardiac MIBG activities have independent but incremental prognostic values in combination with known clinical determinants in patients with heart failure. Systemic inhibition of sympathetic drive and the rennin-angiotension-aldosterone system can improve cardiac MIBG activity and kinetics together with functional improvement in heart failure patients. Prognostic efficacy of contemporary drug treatment is, however, likely to depend on the severity of the impairment of cardiac MIBG activity. Patients who have impaired cardiac MIBG activity with blunted heart rate variability, an elevated brain natriuretic peptide level or LV dysfunction are likely to have appropriate discharges of an implantable cardioverter defibrillator. Thus, cardiac neuroimaging could enable appropriate selection of patients at greater risk for lethal outcomes, who can probably benefit most from pharmacological and invasive strategies.

Limitations of spontaneous reperfusion and conventional medical therapy to afford myocardial protection through antecedent angina pectoris in acute myocardial infarction

Despite the cardioprotective effect of rapid coronary reperfusion, the effects of spontaneous recanalization on myocardial viability and metabolism are unknown. We studied whether preinfarction angina affords cardioprotection when spontaneous coronary reperfusion occurred in acute infarct patients. Myocardial tomographies with thallium and I-123-labeled-β-methyl-p-iodophenyl penta-decanoic acid (BMIPP) were performed in 27 acute myocardial infarct patients treated medically: 15 patients had preexisting angina before infarction (group A) and 12 did not (group B). Thallium and BMIPP abnormalities and regional function were quantified by a polar map and contrast ventriculography, respectively. There was no significant difference between thallium and BMIPP in the severity index in groups A and B (89 ± 97 vs. 85 ± 68, 97 ± 28 vs. 95 ± 27, respectively), and no significant difference between the groups in the thallium or BMIPP severity index. The ratio of the thallium severity index to that of BMIPP and the regional wall-motion abnormality index were identical in groups A and B. Both patient groups were divided into 2 subgroups based on the presence or absence of spontaneous coronary reperfusion: subgroups A1 and A2, and subgroups B1 and B2, respectively. There were no significant differences among the 4 subgroups in severity indexes for both tracers, the thallium/BMIPP ratio, or the asynergy score. The BMIPP severity index correlated significantly with that of thallium in all subgroups, but no significant difference between the regression lines was found. It is therefore unlikely that spontaneous coronary recanalization affords beneficial effects through preservation of myocardial viability in an ischemia-related zone, suggesting that the cardioprotective effect of preinfarction angina is a limited phenomenon in patients undergoing rapid coronary reperfusion.