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.

Cardiac mortality assessment improved by evaluation of cardiac sympathetic nerve activity in combination with hemoglobin and kidney function in chronic heart failure patients.

UNLABELLED: We examined prognostic interactions among cardiac autonomic function assessed by (123)I-labeled metaiodobenzylguanidine ((123)I-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 (123)I-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 (123)I-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 m(2) for estimated GFR. Combining the 4 independent predictors incrementally (P < 0.05) improved prognostic powers maximally up to a global χ(2) 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.

Incremental prognostic value of stress/rest gated perfusion SPECT in patients with coronary artery disease--subanalysis of the J-ACCESS study.

BACKGROUND: This study aimed to reveal the incremental prognostic implications of perfusion/function variables by stress/rest gated single-photon emission computed tomography (SPECT) over clinical risks in patients with known coronary artery disease (CAD). METHODS AND RESULTS: Using the Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT (J-ACCESS) database, the 3-year follow-up data of 2,200 patients who had established CAD were analyzed. Major cardiac events (cardiac death, myocardial infarction, heart failure, and unstable angina) were observed in 167 (7.6%) patients. Multivariate logistic regression analysis identified peripheral artery disease, diabetes mellitus, no use of statins, typical chest pain, pharmacological stress test, heart rate at rest, left ventricular end-systolic volume index derived from gated SPECT (LVESVI), and summed difference score (SDS) as independent significant predictors of the major cardiac events, with odds ratios of 1.025 to 2.291 (P=0.0309-0.0008). Global chi-square values increased by combining the independent predictors, and the greatest values (nearly 110) were observed when LVESVI or SDS was added to the pre-scan clinical information. CONCLUSIONS: Perfusion/function measures by stress/rest gated SPECT contribute to a significant improvement in risk stratification and secondary prevention strategy in combination with pre-scan clinical risks in patients with known CAD.

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.

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.

Predicting the need for an implantable cardioverter defibrillator using cardiac metaiodobenzylguanidine activity together with plasma natriuretic peptide concentration or left ventricular function.

UNLABELLED: 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.

Persistent insulin-sensitizing effects of sarpogrelate hydrochloride, a serotonin 2A receptor antagonist, in patients with peripheral arterial disease.

BACKGROUND: There is considerable interest in the pleiotropic pharmacological action of sarpogrelate hydrochloride, a novel selective serotonin 2A receptor antagonist. In the present study the persistent insulin-sensitizing effects of sarpogrelate were investigated in non-diabetic and non-medicated diabetic patients with peripheral artery disease (PAD). METHODS AND RESULTS: Indices of insulin resistance (IR) (fasting immunoreactive insulin (IRI) and calculated homeostasis model assessment (HOMA-R)) and adiponectin were measured before and after 2 weeks of sarpogrelate administration (300 mg/day) in 24 patients (19 men, 76+/-9 years) with PAD. Sixteen of the 24 patients were examined after 3 months of treatment for assessment of the chronic effect of sarpogrelate on IR. After 2 weeks of treatment, significant decreases in fasting IRI (p=0.03) and HOMA-R (p=0.024), but not in adiponectin, were observed. After 3 months of treatment, significant decreases in fasting IRI (16.0+/-10.3 vs 9.2+/-2.0 microU/ml, p=0.03) and HOMA-R (4.30+/-2.83 vs 2.40+/-0.74, p=0.025) were maintained. Furthermore, adiponectin was significantly increased (8.11+/-4.13 vs 9.64+/-4.37 microg/ml, p=0.027). All of the examined HOMA-R had a significant correlation with all of the examined adiponectin (p<0.001, r=-0.441). CONCLUSIONS: Sarpogrelate has a persistent insulin-sensitizing effect through adiponectin modification and might be beneficial for anti-atherosclerotic therapy, at least, in non-diabetic and non-medicated diabetic patients with PAD.

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

PURPOSE: Although 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. METHODS: Following 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. RESULTS: The 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). CONCLUSION: The 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.

Prognostic implications of an initial loss of cardiac metaiodobenzylguanidine uptake and diabetes mellitus in patients with left ventricular dysfunction.

BACKGROUND: Although altered cardiac sympathetic innervation is related to fatal outcome, the mechanisms and prognostic value of an initial cardiac metaiodobenzylguanidine (MIBG) defect are not known. METHODS AND RESULTS: After quantitative cardiac MIBG imaging, 205 patients with left ventricular ejection fraction <50% were prospectively followed up with a primary end-point of cardiac death for 35 months. In regard to 38 cardiac deaths, consisting of 25 pump failure deaths, 11 sudden deaths, and 2 fatal acute myocardial infarctions, multivariate analysis identified diabetes mellitus as a significant independent predictor as well as reduced cardiac MIBG activity, use of nitrate, and New York Heart Association functional status. Independent of washout kinetics and cardiac function, patients with profound loss of initial MIBG uptake and those with late-phase MIBG activity of 1.74 or less had significantly greater mortality rates than did their counterparts. Initial cardiac MIBG activity closely correlated inversely with annual cardiac death rate. CONCLUSIONS: An initial cardiac MIBG defect and presence of diabetes mellitus indicate a low probability of long-term survival. The profound loss of initial MIBG activity is likely to be due to structural deficit of sympathetic neurons themselves, rather than accelerated sympathetic function, suggesting that denervation is one of mechanisms of cardiac sympathetic dysfunction leading to lethal clinical outcomes.