Effects of mineralocorticoid receptor antagonist eplerenone on cardiac sympathetic nerve activity and left ventricular remodeling after reperfusion therapy in patients with first ST-segment elevation myocardial infarction.

PURPOSE: The activation of the renin-angiotensin-aldosterone system prevents the uptake of norepinephrine and promotes structural remodeling of the heart. The mineralocorticoid receptor antagonist (MRA) eplerenone prevents left ventricular (LV) remodeling in patients with acute myocardial infarction, but its influence on cardiac sympathetic nerve activity (CSNA) has not been determined. METHODS: We retrospectively evaluated the first ST-segment elevation myocardial infarction (STEMI) patients in our database who underwent 123I-metaiodobenzylguanidine (MIBG) scintigraphy 3 weeks after admission. Eighty-four STEMI patients after primary coronary angioplasty were selected, and used propensity score matching to compare patients who treated with MRA (N = 42), and those who did not (N = 42). The LV end-diastolic volume, end-systolic volume, and ejection fraction were determined by echocardiography, and plasma procollagen type III amino terminal peptide (PIIINP) was measured before and 3 weeks after treatment. The delayed total defect score (TDS), delayed heart/mediastinum count (H/M) ratio, and washout rate (WR) were determined using 123I-MIBG scintigraphy after 3 weeks. RESULTS: Following primary angioplasty, age, gender, risk factors, culprit coronary artery, peak serum creatine phosphokinase concentration, and recanalization time were similar in the two groups. However, the MRA group showed significantly lower TDS and WR values (TDS: 22.8 ± 8.1 vs 32.2 ± 11.5, P < 0.005; WR: 31.1 ± 9.0% vs 42.7 ± 9.9%, P < 0.001) and a significantly higher H/M ratio (2.23 ± 0.41 vs 2.03 ± 0.36, P < 0.05) than the non-MRA group. The degree of change in LV parameters, and PIIINP were more favorable in the MRA group than in the non-MRA group. Moreover, multiple linear regression analyses revealed that both WR and not MRA treatment were significant predictor for LV remodeling, along with PIIINP concentrations. CONCLUSION: Administration of eplerenone improves CSNA and prevents LV remodeling in patients with a first STEMI.

Assessment of therapeutic effects of statin on cardiac sympathetic nerve activity after reperfusion therapy in patients with first ST-segment elevation myocardial infarction and normal low-density lipoprotein cholesterol.

BACKGROUND: Statin treatment reduces enhanced cardiac sympathetic nerve activity (CSNA) in patients with heart disease, and reduces adverse cardiac events in patients with coronary artery disease. METHODS: We retrospectively evaluated the first ST-segment elevation myocardial infarction (STEMI) patients and low-density lipoprotein cholesterol < 120 mg/dL in our database who underwent 123I-metaiodobenzylguanidine (MIBG) scintigraphy 3 weeks after admission. Sixty STEMI patients after primary coronary angioplasty were selected, and used propensity score matching to compare patients treated with strong statin (n = 30), and those who did not (n = 30). Moreover, echocardiographic left ventricular (LV) parameters were determined, and plasma procollagen type III amino terminal peptide (PIIINP) was also measured before and 3 weeks after treatment. RESULTS: Following primary angioplasty, age, gender, risk factors, culprit coronary artery, peak serum creatine phosphokinase concentration, and recanalization time were similar in the two groups. However, the statin group showed significantly lower delayed total defect score and washout rate evaluated by 123I-MIBG scintigraphy (22.4 ± 8.1 vs. 29.6 ± 10.5; P < 0.01, and 30.4 ± 8.9% vs. 40.1 ± 11.4%; P < 0.005, respectively) and higher delayed heart/mediastinum count ratio (2.17 ± 0.38 vs. 1.96 ± 0.30, P < 0.05) compared with the non-statin group. Moreover, the degree of change in LV parameters and PIIINP was more favorable in the statin group than in the non-statin group. CONCLUSIONS: Administration of statin improves CSNA after reperfusion therapy in patients with first STEMI.

Most Important Prognostic Values to Predict Major Adverse Cardiovascular, Cerebrovascular, and Renal Events in Patients with Chronic Kidney Disease Including Hemodialysis for 2 Years.

Patients with chronic kidney disease (CKD) have an increased risk of adverse cardiovascular/cerebrovascular events. The aim of this study is to clarify whether stress myocardial perfusion single-photon emission computed tomography (SPECT) could predict cardiovascular/cerebrovascular events. In the Gunma-CKD SPECT Study, a multicenter prospective cohort trial, 311 patients with CKD (estimated glomerular filtration rate < 60 min/mL/1.73 m2) including 50 patients on hemodialysis underwent stress 99mTc-tetrofosmin SPECT for suspected ischemic heart disease and were followed for 2 years. The primary endpoint was the occurrence of cardiac death (CD), while the secondary endpoint was major adverse cardiovascular/cerebrovascular and renal events (MACCRE). MACCRE occurred in 91 out of 286 patients (CD in 13 and other MACCRE in 78 patients). According to a multivariate Cox analysis, hemoglobin (Hb) and end-systolic volume (ESV) were associated with CD (p < 0.05), while the summed difference score, diabetes mellitus (DM), and Hb were associated with MACCRE (p < 0.05). Kaplan-Meier analysis showed that the CD-free rate was higher in patients with ESV < 105 mL (log-rank, p = 0.0013), Hb > 12 g (log-rank, p = 0.0036), and a summed stress score < 6 (log-rank, p = 0.0058). The MACCRE-free rate was higher in patients with SDS = 0 (log-rank, p = 0.0097), without DM (log-rank, p = 0.0091), and with Hb > 12 g (log-rank, p = 0.0023). Myocardial perfusion SPECT parameters as well as renal anemia and DM can be reliable prognostic markers in patients with CKD including hemodialysis.

Adaptive servo-ventilation therapy improves cardiac sympathetic nerve activity, cardiac function, exercise capacity, and symptom in patients with chronic heart failure and Cheyne-Stokes respiration.

PURPOSE: Adaptive servo-ventilation (ASV) therapy has been reported to be effective for improving central sleep apnea (CSA) and chronic heart failure (CHF). The purpose of this study was to clarify whether ASV is effective for CSA, cardiac sympathetic nerve activity (CSNA), cardiac symptoms/function, and exercise capacity in CHF patients with CSA and Cheyne-Stokes respiration (CSR-CSA). METHODS: In this study, 31 CHF patients with CSR-CSA and a left ventricular ejection fraction (LVEF) ≤ 40% were randomized into an ASV group and a conservative therapy (non-ASV) group for 6 month. Nuclear imagings with 123I-Metaiodobenzylguanidine (MIBG) and 99mTc-Sestamibi were performed. Exercise capacity using a specific activity scale (SAS) and the New York Heart Association (NYHA) class were evaluated. CSNA was evaluated by 123I-MIBG imaging, with the delayed heart/mediastinum activity ratio (H/M), delayed total defect score (TDS), and washout rate (WR). RESULTS: The ASV group had significantly better (P < .05) results than the non-ASV group with respect to the changes of AHI (-20.8 ± 14.6 vs -0.5 ± 8.1), TDS (-7.9 ± 4.3 vs 1.4 ± 6.0), and H/M(0.16 ± 0.16 vs -0.04 ± 0.10) on 123I-MIBG imaging, as well as the changes of LVEF (5.3 ± 3.9% vs 0.7 ± 32.6%), SAS (1.6 ± 1.4 vs 0.3 ± 0.7), and NYHA class (2.2 ± 0.4 vs 2.7 ± 0.5) after 6-month therapy. CONCLUSIONS: Performing ASV for 6 months achieved improvement of CSR-CSA, CSNA, cardiac symptoms/function, and exercise capacity in CHF patients with CSR-CSA.

Prognostic value of myocardial perfusion single photon emission computed tomography for major adverse cardiac cerebrovascular and renal events in patients with chronic kidney disease: results from first year of follow-up of the Gunma-CKD SPECT multicenter study.

PURPOSE: Patients with chronic kidney disease (CKD) have an increased risk of adverse cardio-cerebrovascular events. We examined whether stress myocardial perfusion single photon emission computed tomography (SPECT) provides reliable prognostic markers for these patients. METHODS: In this multicenter, prospective cohort trial from the Gunma-CKD SPECT study protocol, patients with CKD [estimated glomerular filtration rate (eGFR) < 60 min/ml per 1.73 m(2)] undergoing stress (99m)Tc-tetrofosmin SPECT for suspected or possible ischemic heart disease were initially followed for 1 year, with the following study endpoints: primary, the occurrence of cardiac deaths (CDs), and secondary, major adverse cardiac, cerebrovascular, and renal events (MACCREs). The summed stress score (SSS), summed rest score, and summed difference score (SDS) were estimated with the standard 17-segment, 5-point scoring model. Left ventricular end-diastolic volume, end-systolic volume (ESV), and ejection fraction were measured using electrocardiogram-gated SPECT. RESULTS: During the first year of follow-up, 69 of 299 patients experienced MACCREs (CD, n = 7; non-fatal myocardial infarction, n = 3; hospitalization for heart failure, n = 13; cerebrovascular accident, n = 1; need for revascularization, n = 38; and renal failure, i.e., hemodialysis initiation, n = 7). ESV and SSS were associated with CDs (p < 0.05), and eGFR and SDS were associated with MACCREs (p < 0.05), in multivariate logistic analysis. Patients with high ESV and high SSS had a significantly higher CD rate during the first year than the other CKD patient subgroups (p < 0.05). Patients with low eGFR and high SDS had a significantly higher MACCRE rate than the other subgroups (p < 0.05). CONCLUSION: Myocardial perfusion SPECT can provide reliable prognostic markers for patients with CKD.

Diastolic Stunning as a Marker of Severe Coronary Artery Stenosis: Analysis by Speckle Tracking Radial Strain in the Resting Echocardiogram.

BACKGROUND: Two-dimensional speckle tracking (2DST) stress echocardiography detects postischemic myocardial diastolic stunning. However, the use of 2DST at rest for detecting diastolic stunning in ischemia is unclear. RESULTS: Thirty-nine patients (age = 65 ± 12 years; male/female = 34/5) with effort angina pectoris that was confirmed by stress myocardial perfusion scintigraphy were enrolled. Ischemic area (I) was determined in the middle LV short axial view using stress myocardial scintigraphy. The area opposite to it was defined as nonischemic area (non-I). Midventricular parasternal short-axis (SAX) radial strains were estimated using 2DST at rest on the following day. LV diastolic function was evaluated using diastolic index (DI, changes in the regional LV radial strain during diastole) and radial strain rate (SR) during early diastolic period. These parameters were compared between I and non-I before and 1 month after percutaneous coronary intervention (PCI) in the I of 3 coronary vessels. For the I, the DI was lower (38 ± 27 vs. 55 ± 27; P = 0.003) and SR was higher (-1.6 ± 0.6 vs. -1.9 ± 0.8; P = 0.007) than in non-I before PCI. One month after PCI, the DI and SR recovered to 53 ± 27 (P = 0.008) and -2.1 ± 0.8 (P = 0.006), respectively. Furthermore, the DI of the LAD and LCX significantly improved (P = 0.0004 and 0.002, respectively); the RCA area showed tendency to improve (P = 0.092), and the SR also improved (P < 0.05) in all areas after PCI. CONCLUSION: Diastolic stunning in ischemic areas can be detected using 2DST at rest and recover 1 month after PCI.

Usefulness of Cardiac Sympathetic Nerve Imaging Using (123)Iodine-Metaiodobenzylguanidine Scintigraphy for Predicting Sudden Cardiac Death in Patients With Heart Failure.

The autonomic nervous system plays an important role in the human heart. Activation of the cardiac sympathetic nervous system is a cardinal pathophysiological abnormality associated with the failing human heart. Myocardial imaging using (123)I-metaiodobenzylguanidine (MIBG), an analog of norepinephrine, can be used to investigate the activity of norepinephrine, the predominant neurotransmitter of the sympathetic nervous system. Many clinical trials have demonstrated that (123)I-MIBG scintigraphic parameters predict cardiac adverse events, especially sudden cardiac death, in patients with heart failure. In this review, we summarize results from published studies that have focused on the use of cardiac sympathetic nerve imaging using (123)I-MIBG scintigraphy for risk stratification of sudden cardiac death in patients with heart failure.

Effects of adding intravenous nicorandil to standard therapy on cardiac sympathetic nerve activity and myocyte dysfunction in patients with acute decompensated heart failure.

PURPOSE: Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, improves cardiac sympathetic nerve activity (CSNA) in ischemic heart disease or chronic heart failure. However, its effects on CSNA and myocyte dysfunction in acute heart failure (AHF) remain unclear. We investigated the effects of adding intravenous nicorandil to standard therapy on CSNA and myocyte dysfunction in AHF. METHODS: We selected 70 patients with mild to moderate nonischemic AHF who were treated with standard conventional therapy soon after admission. Thirty-five patients were assigned to additionally receive intravenous nicorandil (4-12 mg/h; group A), whereas the remaining patients continued their current drug regimen (group B). Delayed total defect score (TDS), delayed heart to mediastinum count (H/M) ratio, and washout rate (WR) were determined by (123)I-metaiodobenzylguanidine (MIBG) scintigraphy within 3 days of admission and 4 weeks later. High sensitivity troponin T (hs-TnT) level was also measured at the same time points. RESULTS: After treatment, MIBG scintigraphic parameters significantly improved in both groups. However, the extent of the changes in these parameters in group A significantly exceeded the extent of the changes in group B [TDS -11.3 ± 4.3 in group A vs -4.0 ± 6.0 in group B (p < 0.01); H/M ratio 0.31 ± 0.16 vs 0.14 ± 0.16 (p < 0.01); WR -13.8 ± 7.8 % vs -6.1 ± 8.9 % (p < 0.01)]. The hs-TnT level decreased significantly from 0.052 ± 0.043 to 0.041 ± 0.033 ng/ml (p < 0.05) in group A, but showed no significant change in group B. Moreover, in both groups, no relationships between the extent of changes in MIBG parameters and hs-TnT level were observed. CONCLUSION: Adding intravenous nicorandil to standard therapy provides additional benefits for CSNA and myocyte dysfunction over conventional therapy alone in AHF patients. Furthermore, the mechanisms of improvement in CSNA and myocyte dysfunction after nicorandil treatment in AHF patients were distinct.

Effects of oral nicorandil therapy on sympathetic nerve activity and cardiac events in patients with chronic heart failure: subanalysis of our previous report using propensity score matching.

PURPOSE: Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, improves cardiac sympathetic nerve activity (CSNA) in patients with ischaemic heart disease. However, the long-term effects on both CSNA, as evaluated by (123)I-metaiodobenzylguanidine (MIBG) scintigraphy, and prognosis have not been determined in patients with chronic heart failure (CHF). METHODS: This study was a subanalysis of our previous results that serial (123)I-MIBG scintigraphic studies are the most useful prognostic indicator in CHF patients. The study group comprised 208 patients with CHF (left ventricular ejection fraction <45 %) but no cardiac events for at least 5 months identified on the basis of a history of decompensated acute heart failure requiring hospitalization. These patients underwent (123)I-MIBG scintigraphy and echocardiography just before leaving the hospital and again 6 months later. We selected 170 patients and used propensity propensity score matching to compare patients who received oral nicorandil (85 patients) and those who did not (85 patients). The patients were followed up for a median of 5.03 years, with the primary and secondary study end-points defined as the occurrence of a fatal cardiac event and a major adverse cardiac event (MACE), respectively. RESULTS: After treatment, the extent of changes in (123)I-MIBG scintigraphic and echocardiographic parameters in the nicorandil group were more favourable than in those not receiving nicorandil. Of the 170 patients, a fatal cardiac event occurred in 42, and a MACE in 68 during the study. Multivariate Cox regression analyses revealed that no nicorandil treatment was a significant predictor of both cardiac death and MACE in our patients with CHF. On Kaplan-Meier analysis, the rates of freedom from cardiac death or from MACE in the nicorandil group were significantly higher than in those not receiving nicorandil (all p<0.05). CONCLUSION: Long-term nicorandil treatment improves CSNA and left ventricular parameters in patients with CHF. Furthermore, this agent is potentially effective for reducing the incidence of cardiac events in patients with CHF.

Evaluation of cardiac sympathetic nerve activity and aldosterone suppression in patients with acute decompensated heart failure on treatment containing intravenous atrial natriuretic peptide.

PURPOSE: Aldosterone prevents the uptake of norepinephrine in the myocardium. Atrial natriuretic peptide (ANP), a circulating hormone of cardiac origin, inhibits aldosterone synthase gene expression in cultured cardiocytes. We evaluated the effects of intravenous ANP on cardiac sympathetic nerve activity (CSNA) and aldosterone suppression in patients with acute decompensated heart failure (ADHF). METHODS: We studied 182 patients with moderate nonischemic ADHF requiring hospitalization and treated with standard therapy containing intravenous ANP and 10 age-matched normal control subjects. ANP was continuously infused for >96 h. In all subjects, delayed total defect score (TDS), heart to mediastinum ratio, and washout rate were determined by 123I-metaiodobenzylguanidine (MIBG) scintigraphy. Left ventricular (LV) end-diastolic volume, end-systolic volume, and ejection fraction were determined by echocardiography. All patients with acute heart failure (AHF) were examined once within 3 days and then 4 weeks after admission, while the control subjects were examined only once (when their hemodynamics were normal). Moreover, for 62 AHF patients, plasma aldosterone concentrations were measured at admission and 1 h before stopping ANP infusion. RESULTS: 123I-MIBG scintigraphic and echocardiographic parameters in normal subjects were more favorable than those in patients with AHF (all p < 0.001). After treatment, all these parameters improved significantly in AHF patients (all p < 0.001). We also found significant correlation between percent changes of TDS and aldosterone concentrations (r = 0.539, p < 0.001) in 62 AHF patients. CONCLUSION: The CSNA and LV performance were all improved in AHF patients. Furthermore, norepinephrine uptake of myocardium may be ameliorated by suppressing aldosterone production after standard treatment containing intravenous ANP.

Combination of ¹²³I-metaiodobenzylguanidine scintigraphy and flow-mediated dilation for the detection of patients with coronary spastic angina.

BACKGROUND: This study evaluated the usefulness of cardiac sympathetic nerve activity, estimated by (123)I-MIBG scintigraphy, and endothelial function, estimated by flow-mediated dilation (FMD), in the detection of coronary spastic angina (CSA). METHODS AND RESULTS: We compared 78 consecutive patients suspected of CSA with ten age-matched controls. On the basis of a spasm provocation test with acetylcholine, 53 patients were diagnosed as CSA and 25 patients were considered to have chest-pain syndrome (CPS). The total defect score (TDS) by delayed (123)I-MIBG scintigraphy was significantly higher in both patient groups than in controls (P < 0.05), and was significantly higher in CSA than in CPS patients (P = 0.02). The heart/mediastinum activity (H/M) ratio by delayed (123)I-MIBG scintigraphy and FMD were significantly lower in both patient groups than in controls (P < 0.05), and were lower in CSA than in CPS patients (P = 0.04). In receiver-operating curve analysis, the areas under the curve for TDS, H/M, and FMD were 0.78, 0.72, and 0.70, respectively. The combination of delayed (123)I-MIBG scintigraphy and FMD showed a higher diagnostic value than either method alone. CONCLUSIONS: (123)I-MIBG scintigraphy and FMD can distinguish CSA patients among patients complaining of chest pain at rest, with good sensitivity and specificity.

Relationship between late ventricular potentials and myocardial 123I-metaiodobenzylguanidine scintigraphy in patients with dilated cardiomyopathy with mild to moderate heart failure: results of a prospective study of sudden death events.

PURPOSE: Late ventricular potentials (LPs) are considered to be useful for identifying patients with heart failure at risk of developing ventricular arrhythmias. (123)I-metaiodobenzylguanidine (MIBG) scintigraphy, which is used to evaluate cardiac sympathetic activity, has demonstrated cardiac sympathetic denervation in patients with malignant ventricular tachyarrhythmias. This study was undertaken to clarify the relationship between LPs and (123)I-MIBG scintigraphy findings in patients with dilated cardiomyopathy (DCM). METHODS: A total of 56 patients with DCM were divided into an LP-positive group (n = 24) and an LP-negative group (n = 32). During the compensated period, the delayed heart/mediastinum count (H/M) ratio, delayed total defect score (TDS), and washout rate (WR) were determined from (123)I-MIBG images and plasma brain natriuretic peptide (BNP) concentrations were measured. Left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and left ventricular ejection fraction (LVEF) were simultaneously determined by echocardiography. RESULTS: LVEDV, LVESV, LVEF and plasma BNP concentrations were similar in the two groups. However, TDS was significantly higher (35 ± 8 vs. 28 ± 6, p < 0.005), the H/M ratio was significantly lower (1.57 ± 0.23 vs. 1.78 ± 0.20, p < 0.005), and the WR was significantly higher (60 ± 14% vs. 46 ± 12%, p < 0.001) in the LP-positive than in the LP-negative group. The average follow-up time was 4.5 years, and there were nine sudden deaths among the 56 patients (16.1%). In logistic regression analysis, the incidences of sudden death events were similar in those LP-negative with WR <50%, LP-negative with WR ≥ 50% and LP-positive with WR <50% (0%, 10.0% and 14.3%, respectively), but was significantly higher (41.2%) in those LP-positive with WR ≥ 50% (p < 0.01, p < 0.05, and p < 0.05, respectively). CONCLUSION: The present study demonstrated that the values of cardiac (123)I-MIBG scintigraphic parameters were worse in LP-positive DCM patients than in LP-negative DCM patients. Furthermore, in LP-positive DCM patients with a high WR, the incidence of sudden death events was higher than that in other subgroups of DCM patients.

Olmesartan improves coronary flow reserve of hypertensive patients using coronary magnetic resonance imaging compared with amlodipine.

OBJECTIVES: Hypertension impairs coronary endothelial cell function, coronary microvascular function and the coronary flow (CF) reserve (CFR). Angiotensin II receptor blockers (ARBs) have been reported to possibly improve coronary endothelial function and coronary microvascular function. The purpose of this study was to determine whether treatment with the ARB olmesartan was more effective for improving CFR than the calcium channel blocker amlodipine. METHODS: Twenty patients with untreated essential hypertension (M/F = 13/7, aged 55.6 ± 11.6 years) were randomly assigned to treatment with either olmesartan (n = 10) or amlodipine (n = 10) for 6 months. CF was measured in the proximal left anterior descending artery by magnetic resonance imaging before and during intravenous infusion of adenosine. CFR was calculated as the ratio of the hyperemic to baseline diastolic peak flow before and after 6 months of treatment. RESULTS: The extent of systolic blood pressure reduction was similar in both groups (-40.0 ± 19.1 vs. -48.8 ± 14.7 mm Hg, p = 0.26). The olmesartan group showed significant improvement of CFR (from 1.9 ± 1.0 to 3.1 ± 1.1, p = 0.005), but this did not occur in the amlodipine group. CONCLUSION: Olmesartan, but not amlodipine, improves CFR in hypertensive patients.

Relation between connective tissue growth factor and cardiac sympathetic nerve activity in heart failure in DCM patients.

Cardiac fibrosis is an important process of myocardial remodeling. Connective tissue growth factor (CTGF) is a cytokine that plays a key role in the occurrence of progressive fibrosis and excessive scarring. CTGF levels are increased in the failing heart. In addition, sympathetic nerve activity is enhanced in the failing heart, and exacerbates heart failure. To clarify the relation between cardiac sympathetic nerve activity and CTGF, we studied 35 (M/F = 28/7 patients) aged 57 ± 15 years with dilated cardiomyopathy (DCM). Cardiac sympathetic nerve activity was estimated from the total defect score (TDS) and from the H/M ratio and washout rate (WR) on I-123-MIBG imaging. Cardiac symptoms (NYHA class), exercise capacity (specific activity scale: SAS), brain natriuretic peptide (BNP), hemodynamics, and CTGF were assessed. There was a significant correlation between the CTGF and WR on I-123-MIBG (r = 0.45, P = 0.008). Also, a higher plasma CTGF level was associated with a lower SAS score (r = 0.51, P = 0.002), but not the TDS, H/M ratio, or BNP concentration. Moreover, a higher NYHA class and pulmonary artery wedge pressure were associated with a higher plasma CTGF level. The plasma CTGF level can be strongly related with cardiac sympathetic nerve activity in heart failure in DCM patients.

Low-dose and long-term G-CSF treatment can improve severe myocardial ischemia in patients with severe coronary artery disease.

BACKGROUND: It has been reported that granulocyte colony-stimulating factor (G-CSF) can promote angiogenesis by mobilizing bone marrow stem cells to blood vessels. The purpose of this study is to clarify whether low-dose and long-term G-CSF treatment can improve severe myocardial ischemia. METHODS: We studied 40 patients (M/F = 29/11, age = 68 ± 9 years) who had severe coronary artery disease (7 with and 5 without old myocardial infarction; 3VD/2VD/1VD = 17/17/6) and severe myocardial ischemia with no indication for revascularization. G-CSF (1.5 µg/kg) was injected for 14 consecutive days. All patients were evaluated using stress myocardial scintigraphy, the Canadian Cardiovascular Society (CCVS) score, and cardiopulmonary exercise testing before and after 3 months of treatment. On 17 SPECT segments, the total defect score (TDS) and delta TDS (TDS (stress) minus TDS (resting)) were evaluated to assess the severity of myocardial ischemia. RESULTS: The changes in stress TDS, delta TDS, and regional wall motion score were significantly greater in the G-CSF group than the control group (P < .0001). The CCVS score improved significantly from baseline to the 3-month follow-up assessment in the G-CSF group (P < .0001). The increase of peak VO2 was significantly larger in the G-CSF group than the control group (P = .015). CONCLUSION: Low-dose and long-term G-CSF treatment can improve severe ischemia in patients with severe coronary artery disease.

Efficacy of Add-on Therapy with Carvedilol and the Direct Renin Inhibitor Aliskiren for Improving Cardiac Sympathetic Nerve Activity, Cardiac Function, Symptoms, Exercise Capacity and Brain Natriuretic Peptide in Patients with Dilated Cardiomyopathy.

Purpose/Method: Aliskiren is a direct renin inhibitor that has been reported to be effective for CHF, but the usefulness of combined therapy with carvedilol and aliskiren has not been reported. Forty-four patients with dilated cardiomyopathy (DCM) were randomized into a group receiving add-on therapy with carvedilol plus aliskiren and another group receiving carvedilol alone for 6 months. Nuclear imagings with 123I-Metaiodobenzylguanidine (MIBG) and 99mTc-Sestamibi were performed. Exercise capacity using a specific activity scale (SAS) and the New York Heart Association (NYHA) class were evaluated. Cardiac sympathetic nerve activity was evaluated by 123I-MIBG imaging, with the delayed heart-to-mediastinum activity ratio (H/M), delayed total defect score (TDS), and washout rate (WR). Results: Combined add-on therapy with carvedilol and aliskiren improved several parameters much more than carvedilol alone (p<0.05) with respect to TDS, ejection fraction (EF), NYHA, SAS on 6 months and the changes in TDS, EF, end-diastolic volume and brain natriuretic peptide (BNP). Conclusion: Add-on therapy with carvedilol and aliskiren is more effective than carvedilol alone for improving cardiac sympathetic nerve activity, cardiac function, symptoms, exercise capacity, and brain natriuretic peptide in patients with DCM.

A 2-Year Prospective Study on the Differences in Prognostic Factors for Major Adverse Cardiovascular, Cerebrovascular and Renal Events Between Patients with Mild and Severe Chronic Kidney Disease.

Purpose/Method: No studies have reported on prognostic markers in patients with chronic kidney disease (CKD) according to the severity of the disease. Therefore, in this multicenter, prospective trial performed as part of the Gunma CKD SPECT Multicenter Study, we recruited 311 patients with CKD (eGFR < 60 min/mL/1.73 m2) including 50 patients on hemodialysis and followed them for 2 years. The study sample underwent stress 99mTc-tetrofosmin SPECT for suspected or possible ischemic heart disease. We evaluated the summed stress score (SSS), summed rest score (SRS), summed difference score (SDS) and cardiac function with electrocardiogram-gated SPECT. Then, we compared the differences in prognostic markers for major adverse cardiac, cerebrovascular, and renal events (MACCRE) between patients with mild CKD (30 min/mL/1.73 m2 ≤ eGFR <60 min/mL/1.73 m2; n=184) and those with severe CKD (eGFR <30 min/mL/1.73 m2; n=97). Results: Of 281 patients available for analysis, 91 experienced MACCRE. In a multivariate Cox proportional hazards analysis of factors related to MACCRE, in patients with mild CKD the significant prognostic markers were SDS (P=0.002) and end-systolic volume (ESV, P=0.034); and in the patients with severe CKD, they were eGFR (P=0.03) and diabetes-mellitus (DM, P=0.023). Conclusions: Our findings indicate that SDS and ESV are significant prognostic markers for MACCRE in patients with mild CKD and eGFR and DM are significant prognostic markers in patients with severe CKD.

Magnetic resonance imaging is superior to cardiac scintigraphy to identify nonresponders to cardiac resynchronization therapy.

BACKGROUND: Left ventricular (LV) postero-lateral scar and total scar burden are factors responsible for a poor response to cardiac resynchronization therapy (CRT). Contrast-enhanced magnetic resonance imaging (CMR) and (99m)Tc-2-methoxy isobutyl isonitrile single photon emission computed tomography (SPECT) perfusion imaging are widely used to detect myocardial scar tissue; however, their ability to detect regional scars and predict a positive response to CRT has not been fully evaluated. METHODS: CMR and SPECT were performed in 17 patients with dilated cardiomyopathy (DCM) and seven patients with ischemic cardiomyopathy (ICM) before CRT. All images were scored, using a 17-segment model. To analyze the LV scar regions by CMR, we assessed the transmural delayed enhancement extent as the transmural score in each segment (0 = no scar, 4 = transmural scar). Similarly, a perfusion defect score was assigned to each segment by SPECT (0 = normal uptake, 4 = defect). RESULTS: By both SPECT and CMR imaging, the total scar score was significantly higher in the ICM than in the DCM group. An LV postero-lateral wall scar region was detected using both imaging modes. By SPECT imaging, the percentage of regional scar score in the LV inferior wall was significantly higher in the DCM than in the ICM group. CONCLUSIONS: By SPECT imaging in the DCM group, severe perfusion defects, due to attenuation artifacts, were frequently observed in the LV inferior wall, resulting in the overestimation of scar tissue. CMR identified nonresponders to CRT more reliably than SPECT in patients with DCM.

Effect of atrial natriuretic peptide on left ventricular remodelling in patients with acute myocardial infarction.

Atrial natriuretic peptide (ANP) is a member of the natriuretic peptide family that exerts various biological effects via acting on the receptor-guanylyl cyclase system, increasing the content of intracellular cyclic guanosine monophosphate (cGMP). ANP was first identified as a diuretic/natriuretic and vasodilating hormone, but subsequent studies revealed that ANP has a very important function in the inhibition of the renin-angiotensin-aldosterone system (RAAS), endothelin synthesis, and sympathetic nerve activity. Evidence is also accumulating from recent work that ANP exerts its cardioprotective functions not only as a circulating hormone but also as a local autocrine and/or paracrine factor. ANP inhibits apoptosis and hypertrophy of cardiac myocytes, and inhibits proliferation and fibrosis of cardiac fibroblasts. Reperfusion of the ischaemic myocardium by percutaneous coronary intervention (PCI) reduces the infarct size and improves left ventricular (LV) function in patients with acute myocardial infarction (AMI). However, the benefits of PCI in AMI are limited by reperfusion injury. Animal studies have shown that ANP inhibits ischaemia/reperfusion injury, and reduces infarct size. We and others have recently shown that the intravenous administration of ANP inhibits RAAS, sympathetic nerve activity and reperfusion injury, prevents LV remodelling, and improves LV function in patients with AMI. ANP has a variety of cardioprotective effects and is considered to be a very promising adjunct drug for the reperfusion therapy in patients with AMI.