Prognostic Implications of Sarcoidosis Granulomas　- Insights From the Multicenter Registry, the Japanese Cardiac Sarcoidosis Prognostic Study.

Background: Definitions of cardiac sarcoidosis (CS) differ among guidelines. Any systemic histological finding of CS is essential for the diagnosis of CS in the 2014 Heart Rhythm Society statement, but not necessary in the Japanese Circulation Society 2016 guidelines. This study aimed to reveal the differences in outcomes by comparing 2 groups, namely CS patients with or without systemic histologically proven granuloma. Methods and Results: This study retrospectively included 231 consecutive patients with CS. CS with granulomas in ≥1 organs was diagnosed in 131 patients (Group G), whereas CS without any granulomas was diagnosed in the remaining 100 patients (Group NG). Left ventricular ejection fraction (LVEF) was significantly reduced in Group NG compared with Group G (44±13% vs. 50±16%, respectively; P=0.001). However, Kaplan-Meier curves showed that major adverse cardiovascular events (MACE)-free survival outcomes were comparable between the 2 groups (log-rank P=0.167). Univariable analyses showed that significant predictors of MACE were Groups G/NG, histological CS, LVEF, and high B-type natriuretic peptide (BNP) or N-terminal pro BNP concentrations, but none of these was significant in multivariable analyses. Conclusions: Overall risks of MACE were similar between the 2 groups despite different manifestations in cardiac dysfunction. The data not only validate the prognostic value of non-invasive diagnosis of CS, but also show the need for careful observation and therapeutic strategy in patients with CS without any granuloma.

Interaction of impaired myocardial flow reserve and extent of myocardial ischemia assessed using 13N-ammonia positron emission tomography imaging on adverse cardiovascular outcomes.

BACKGROUND: Myocardial flow reserve (MFR) and the extent of myocardial ischemia identify patients at high risk of major adverse cardiovascular events (MACEs). Associations between positron emission tomography (PET)-assessed extent of ischemia, MFR, and MACEs is unclear. METHOD: Overall, 640 consecutive patients with suspected or known coronary artery disease undergoing 13N-ammonia myocardial perfusion PET were followed-up for MACEs. Patients were categorized into three groups based on myocardial ischemia severity: Group I (n = 335), minimal (myocardial ischemia < 5%); Group II (n = 150), mild (5-10%); and Group III (n = 155), moderate-to-severe (> 10%). RESULTS: Cardiovascular death and MACEs occurred in 17 (3%) and 93 (15%) patients, respectively. Following statistical adjustment for confounding factors, impaired MFR (global MFR < 2.0) was revealed as an independent predictor of MACEs in Groups I (hazard ratio [HR], 2.89; 95% confidence interval [CI], 1.48-5.64; P = 0.002) and II (HR, 3.40; 95% CI 1.37-8.41; P = 0.008) but was not significant in Group III (HR, 1.15; 95% CI 0.59-2.26; P = 0.67), with a significant interaction (P < 0.0001) between the extent of myocardial ischemia and MFR. CONCLUSION: Impaired MFR was significantly associated with increased risk of MACEs in patients with ≤ 10% myocardial ischemia but not with those having > 10% ischemia, allowing a clinically effective risk stratification.

Multicenter Registry in the Japanese Cardiac Sarcoidosis Prognostic (J-CASP) Study: Baseline Characteristics and Validation of the Non-invasive Approach Using 18F-FDG PET.

Background: Recent advances in cardiac modalities contribute to the guidelines on the diagnosis of cardiac sarcoidosis (CS) updated by the Japanese Circulation Society. The multicenter registry, Japanese Cardiac Sarcoidosis Prognostic (J-CASP) study tried to reveal recent trends of diagnosis and outcomes in CS patients and to validate the non-invasive diagnostic approach, including cardiac 18F-fluorodeoxyglucose (FDG) study. Methods/results: Databases from 12 hospitals consisting of 231 CS patients (mean age, 64 years; female, 65%; LV ejection fraction, 47%) diagnosed by the guidelines with FDG positron emission tomography (PET) study were integrated to compile clinical information on the diagnostic criteria and outcomes. Cardiac 18F-FDG uptake and magnetic resonance imaging (CMR) was positive identically in the histology-proven and clinically-diagnosed groups. The histology-proven group more frequently had reduce LV ejection fraction, myocardial perfusion abnormality and low-grade electrocardiogram (ECG) abnormality (P=0.003 to 0.016) than did the clinical group. During a 45-month period, the histology-proven group more frequently underwent appropriate implantable cardioverter-defibrillator (ICD) treatment (14% versus 4%, P=0.013) and new electronic device implantation (30% versus 12%, P=0.007) than did clinical group, respectively. There, however, was no difference in all-cause or cardiac mortality or in new hospitalization due to heart failure progression between them. Conclusion: The J-CASP registry demonstrated the rationale and clinical efficacies of non-invasive approach using advanced cardiac imaging modalities in the diagnosis of CS even when histological data were available.

Association of the extent of myocardial ischemia with outcomes in patients with suspected coronary artery disease in Japan.

BACKGROUND: There is an ongoing controversy regarding the necessity of single-photon emission computed tomography (SPECT) for patients with ischemic heart diseases after the publication of the results of the ISCHEMIA trial. We aimed to evaluate the association of the extent of myocardial ischemia with outcomes in patients with suspected coronary artery disease in Japan. METHODS: From the data of 2780 patients with stable angina who were enrolled prospectively between January 2006 and March 2008 in Japan and had undergone physician-referred non-invasive imaging tests (Japanese Coronary-Angiography or Myocardial Imaging for Angina Pectoris Study), 1205 patients managed with SPECT were stratified by 10 % myocardial ischemia. Major adverse cardiac events (MACEs), including death, myocardial infarction, hospitalization for heart failure, and late revascularization, were followed-up for 1 year. RESULTS: Patients with ≥10 % myocardial ischemia (n = 173) were less likely to be women than patients with <10 % myocardial ischemia (n = 1032) and had a significantly higher 1-year cumulative incidence of MACEs (6.9 % vs. 1.8 %, p < 0.0001). After adjusting for confounders, the risk of ≥10 % myocardial ischemia relative to <10 % myocardial ischemia for MACEs remained significant [adjusted hazard ratio (95 % confidence interval), 2.40 (1.09-5.26), p = 0.029]. After adjusting including treatments, the risk of MACEs became insignificant between the ≥10 % myocardial ischemia group and the <10 % myocardial ischemia group [adjusted hazard ratio (95 % confidence interval), 1.04 (0.45-2.45), p = 0.92]. CONCLUSION: The presence of ≥10 % myocardial ischemia at diagnosis was significantly associated with the 1-year risk for MACEs in Japanese patients with suspected coronary artery disease.

Prognostic value of modified coronary flow capacity by 13N-ammonia myocardial perfusion positron emission tomography in patients without obstructive coronary arteries.

BACKGROUND: Vasodilator capacity of coronary circulation is an important diagnostic and prognostic tool in patients with coronary artery disease (CAD). We aimed to clarify the incidence of coronary microvascular dysfunction (CMD), defined as impaired modified coronary flow capacity (mCFC) proposed by Johnson and Gould and measured by 13N-ammonia myocardial perfusion positron emission tomography (PET), in patients without obstructive CAD and to evaluate the risk of future cardiovascular events. METHODS: This retrospective study recruited 407 consecutive CAD-suspected patients who underwent both pharmacological stress/rest 13N-ammonia PET and coronary angiography. Of the 407 patients, 137 patients (median age, 70 years; 63 women) were eligible and followed up (median, 19.8 months). Endpoints were defined as cardiovascular death or major adverse cardiovascular events (MACEs), such as cardiovascular death, nonfatal myocardial infarction, unplanned hospitalization for any cardiac reasons, and unplanned coronary revascularization. The impaired mCFC group included patients with mildly to severely reduced regional CFC in, at least, one vascular territory (n=34), while the remaining patients (n=103) were categorized as having preserved mCFC. RESULTS: Overall, cardiovascular death and MACEs occurred in five (4%) patients. The Kaplan-Meier curve showed a significant reduction in event-free survival for cardiovascular death (p=0.004) and MACEs (p<0.0001) in the impaired mCFC group, compared to the preserved mCFC group. Impaired mCFC was independently associated with the incidence of both cardiovascular death and MACEs after propensity-score adjustments [hazard ratio (HR), 10.7; 95% confidence interval (CI), 1.0-106.0; p=0.04 and HR, 9.5; 95% CI, 2.5-36.2; p<0.001, respectively]. CONCLUSIONS: In CAD-suspected patients without obstructive coronary arteries, impaired mCFC was observed in approximately 25% and was associated with a higher risk of cardiovascular death and MACEs. The mCFC concept can help identify patients who would benefit from specific therapies or lifestyle modifications to prevent future MACEs and can clarify potential mechanisms of CMD.

Texture analysis of delayed contrast-enhanced computed tomography to diagnose cardiac sarcoidosis.

PURPOSE: To investigate the diagnostic value of texture analysis to differentiate cardiac sarcoidosis (CS) from other non-ischemic cardiomyopathies (non-CS). MATERIALS AND METHODS: Twenty CS patients and 15 non-CS patients who had undergone myocardial CT delayed enhancement (CTDE) were included. A total of 36 texture features were calculated according to the CT attenuation of CTDE. We investigated the diagnostic value to differentiate CS from non-CS. We also assessed the intra- and inter-rater reproducibility for each feature and inter-observer agreement for visual assessment. RESULTS: Seven extracted features had significantly higher run length non-uniformity (RLNU) values (5.4 × 102 ± 6.2 × 102 vs. 11.2 × 102 ± 4.9 × 102, p = 0.037) and significantly lower low gray-level zone emphasis (LGZE) values (7.1 × 10-3 ± 8.6 × 10-3 vs. 18.1 × 10-3 ± 16.9 × 10-3, p = 0.017) in CS than in non-CS. Intra- and inter-rater reproducibility of RLNU and LGZE were excellent (ICCs > 0.8), while inter-observer agreement of visual assessment was poor (kappa = 0.19). The accuracies of texture analysis were 69% with RLNU and 71% with LGZE, which were better than that of visual assessment. CONCLUSION: Texture analysis of CTDE could differentiate CS from non-CS with high reproducibility.

Elevated serum endothelin-1 is an independent predictor of coronary microvascular dysfunction in non-obstructive territories in patients with coronary artery disease.

Endothelin-1 contributes to the constrictor response of the coronary arteries in patients with ischemia with normal coronary arteries. There is thus increasing evidence that endothelin-1 plays a role in coronary microvascular dysfunction (CMD). We investigated whether elevated endothelin-1 is associated with CMD in patients with coronary artery disease (CAD). We prospectively studied 49 consecutive CAD patients with 1- or 2-vessel disease (age 71 ± 10 years, 43 males). Myocardial blood flow (MBF) was measured by 15O-water PET/CT at rest and during stress, and the coronary flow reserve (CFR) was calculated by dividing the stress MBF by the rest MBF. A CFR of less than 2.0 in non-obstructive regions was defined as a marker of CMD. Eighteen out of 49 (37%) CAD patients had CMD. Endothelin-1 in patients with CMD was significantly higher than in those without CMD (2.27 ± 0.81 vs. 1.64 ± 0.48 pg/mL, P = 0.001). Accordingly, univariate ROC analysis showed that the continuous endothelin-1 levels significantly discriminated between the presence and absence of CMD (area under the curve = 0.746 [95%CI 0.592-0.899]). The dichotomous treatment of elevated endothelin-1 as 1.961 pg/mL or more yielded the optimal discriminatory capacity, with a sensitivity of 72.2% and a specificity of 71.0%. High endothelin-1 was still a significant predictor of CMD after adjusting for diabetes mellitus (odds ratio = 6.64 [1.75-25.22], P = 0.005). Endothelin-1 is associated with CMD in non-obstructive territories in patients with CAD, suggesting that endothelin-1 is a potential target for treating CMD in CAD patients.

Prognostic value of phase analysis on gated single photon emission computed tomography in patients with cardiac sarcoidosis.

BACKGROUND: We aimed to determine the correlation between phase analysis, reflecting the heterogeneity of perfusion defects, and the dyssynchrony of the left ventricle wall motion, and adverse cardiac events in cardiac sarcoidosis (CS) patients. METHODS: Fifty-seven consecutive patients with diagnosed CS (64 [IQR 55-71] years old, 14 males), who underwent 18F-FDG PET/CT and ECG-gated SPECT, were studied. FDG PET was analysed to measure cardiac metabolic volume (CMV), and total lesion glycolysis (TLG). The SPECT findings, such as LVEF, Summed Rest Score (SRS), bandwidth (BW) were evaluated. RESULTS: The median of BW was 56° (IQR 40-95). BW showed a strong inverse correlation with LVEF (r = - 0.60, P < 0.0001), and positive correlation with SRS (r = 0.82, P < 0.0001). However, there were no significant correlations between BW and CMV or TLG. The Kaplan-Meier curves revealed a significantly higher rate of MACE in the high BW group (BW > 56°) than the low BW group (BW ≤ 56°) (15.1%/years vs. 4.4%/years, P = 0.025). In multivariable analysis, BW was a significant independent predictor of MACE (P = 0.015). CONCLUSION: Phase analysis on gated SPECT was a significant and independent predictor of MACE in patients with CS.

The rate of myocardial perfusion recovery after steroid therapy and its implication for cardiac events in cardiac sarcoidosis and primarily preserved left ventricular ejection fraction.

BACKGROUND: Sarcoidosis is a multisystemic disorder of unknown cause characterized by immune granuloma formation in the involved organs. Few studies have reported on the myocardial perfusion changes by immunosuppression therapy in cardiac sarcoidosis (CS). Additionally, the relationship between myocardial perfusion changes and prognosis is unknown. Therefore, this study aimed to clarify myocardial perfusion recovery after steroid therapy and its prognostic value for major adverse cardiac events (MACE) in patients with CS. METHODS AND RESULTS: Thirty-eight consecutive patients with CS {median age, 63 [interquartile range (IQR) 51-68] years; 10 men} underwent both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (CT) and electrocardiography-gated single-photon emission CT (SPECT) pre- and post-steroid therapy. Patients with improved or preserved myocardial perfusion after post-therapy were defined as the recovery group and those with worsened myocardial perfusion as the non-recovery group. Twenty-six patients (68%) were categorized as the recovery group. MACE occurred in eight patients. The Kaplan-Meier curves revealed a significantly higher rate of MACE in the non-recovery group (17.4%/y vs 2.9%/y, P = 0.007). CONCLUSIONS: Myocardial perfusion was recovered by steroid therapy in 61% and preserved in 8% of patients. Myocardial perfusion recovery after steroid therapy was significantly associated with a low incidence of MACE.

18F-FMISO PET/CT detects hypoxic lesions of cardiac and extra-cardiac involvement in patients with sarcoidosis.

BACKGROUND: 18F-fluoromisonidazole (FMISO) is a hypoxia positron emission tomography (PET) tracer. Here, we evaluated cardiac and extra-cardiac sarcoidosis using both FMISO and 18F-fluorodeoxyglucose (FDG) PET/CT in a prospective cohort of patients with sarcoidosis. METHODS: Ten consecutive sarcoidosis patients with suspected cardiac involvement were prospectively enrolled. Each patient fasted overnight (for ≥ 18 hours) preceded by a low-carbohydrate diet before FDG PET/CT but not given special dietary instructions before the FMISO PET/CT scan. We visually and semiquantitatively assessed the uptakes of FMISO and FDG using the maximal standardized uptake value (SUVmax). The metabolic volume (MV) of FDG was calculated as the volume within the boundary determined by the threshold (mean SUV of blood pool × 1.5). RESULTS: Nine patients showed focal FDG uptake in the myocardium and were diagnosed with cardiac sarcoidosis. Among the patients with extra-cardiac lesions, FDG uptake was seen in 8 lymph nodes and 3 lung lesions. FMISO uptake was seen in the 7 cardiac (77.8%) and 6 extra-cardiac (54.5%) lesions. None of the patients showed physiological FMISO uptake in the myocardium. The SUVmax values of the lesions with FMISO uptake were higher than those of the lesions without FMISO uptake in both the cardiac (SUVmax: 9.9, IQR: 8.4-10.0 vs 7.3, IQR: 6.3-8.2) and non-cardiac lesions (SUVmax: 17.6, IQR: 14.5-19.3 vs 6.1, IQR: 5.9-6.2; P = 0.006). The MV values of the lesions with FMISO uptake were significantly higher than those of the lesions without FMISO uptake (111.3, IQR: 78.3-135.7 vs 6.4, IQR: 1.9-23.3; P = 0.0009). CONCLUSIONS: FMISO showed no physiological myocardial uptake and did not require special preparation. FMISO PET has the potential to detect hypoxic lesions in patients with sarcoidosis.

Functional Assessment of Coronary Artery Disease by Myocardial Flow Reserve Versus Pressure-wire Based Assessment: A Systematic Review.

Positron emission tomography (PET) permits the noninvasive quantification of myocardial blood flow (MBF). Myocardial flow reserve (MFR), calculated by dividing stress MBF by rest MBF is a reliable index for the functional information of coronary artery disease. A pressure-derived physiological index, such as fractional flow reserve (FFR) is also an important measurement. Both MFR and FFR values are used to evaluate coronary physiology; however, but they are not interchangeable because each test has certain discrepancies. In this systematic review, we provide an overview of coronary physiology with PET compared to pressure-derived physiological indices.

Recent advances in cardiac positron emission tomography for quantitative perfusion analyses and molecular imaging.

Positron emission tomography (PET) has been used to noninvasively evaluate myocardial perfusion and metabolism. For clinical assessments of myocardial perfusion, the quantitative capability of PET permits precise assessments of ischemia and microcirculatory dysfunction, playing an important role in patient management and outcome analyses. 18F-fluorodeoxyglucose (FDG) PET has recently been used to identify active cardiovascular lesions such as cardiac sarcoidosis, endocarditis, and aortitis. This may hold promise for the early and accurate diagnosis of such fatal diseases, as well as for patient management. This review covers new and clinical roles of cardiac PET in treatment strategies and patient outcomes.

Association of coronary revascularisation after physician-referred non-invasive diagnostic imaging tests with outcomes in patients with suspected coronary artery disease: a post hoc subgroup analysis.

OBJECTIVE: We aimed to evaluate the association of the prognostic impact of coronary revascularisation with physician-referred non-invasive diagnostic imaging tests (single photon emission CT (SPECT) vs coronary CT angiography) for coronary artery disease. DESIGN: A post hoc analysis of a subgroup from the patient cohort recruited for the Japanese Coronary-Angiography or Myocardial Imaging for Angina Pectoris Study. SETTING: Multiple centres in Japan. PARTICIPANTS: From the data of 2780 patients with stable angina, enrolled prospectively between January 2006 and March 2008 in Japan, who had undergone physician-referred non-invasive imaging tests, 1205 patients with SPECT as an initial strategy and 625 with CT as an initial strategy were analysed. We assessed the effect of revascularisation (within 90 days) in each diagnostic imaging stratum and the interaction between the two strata. PRIMARY AND SECONDARY OUTCOME MEASURES: Major adverse cardiac events (MACEs), including death, myocardial infarction, hospitalisation for heart failure and late revascularisation, were followed up for 1 year. The χ2 test, Student's t-test, Kaplan-Meier analysis, log-rank test and multivariable Cox proportional hazard model were used in data analysis. RESULTS: A total of 210 (17.4%) patients in the SPECT stratum and 149 (23.8%) in the CT stratum underwent revascularisation. Although in each stratum, the cumulative 1 year incidence of MACEs was significantly higher in patients who underwent revascularisation than in those who did not (SPECT stratum: 9.1 vs 1.2%, log-rank p<0.0001; CT stratum: 6.1 vs 0.8%, log-rank p=0.0001), there was no interaction between the risk of revascularisation and the imaging strata (SPECT stratum: adjusted HR (95% CI), 4.25 (1.86-9.72); CT stratum: 4.13 (1.16-14.73); interaction: p=0.97). CONCLUSION: The association of revascularisation with the outcomes of patients with suspected coronary artery disease was not different between SPECT-first and CT-first strategies in a physician-referred fashion.

Validation of regional myocardial blood flow quantification using three-dimensional PET with rubidium-82: repeatability and comparison with two-dimensional PET data acquisition.

INTRODUCTION: Three-dimensional (3D) data acquisition is now standard on PET/computed tomography scanners. The aim of this study was to evaluate the repeatability of myocardial blood flow (MBF) estimation with rubidium-82 (Rb) 3D PET and to validate regional MBF measurements by comparison with two-dimensional (2D) PET. PATIENTS AND METHODS: Fifteen healthy individuals (31.6 ± 11.4 years old) were enrolled for the evaluation of the short-term repeatability of rest 3D MBF quantification. Another 19 healthy individuals (35.3 ± 12.6 years old) underwent rest and pharmacological stress PET using 2D and 3D data acquisition within a 1-month interval. The injected dose was 1500 MBq for 2D and 555 MBq for 3D PET acquisition. RESULTS: MBF at rest showed good repeatability [whole left ventricular MBF; 0.54 ± 0.13 vs. 0.52 ± 0.13 mL/min/g, P = 0.98]. Rest MBF, stress MBF, and myocardial flow reserve (MFR) were not significantly different between 3D and 2D data acquisition. 3D MBF correlated well with 2D MBF over a wide flow range for both whole left ventricular (r = 0.97, P < 0.0001) and regional values (r = 0.61, P < 0.0001). CONCLUSION: MBF measured with 3D PET showed very good test-retest repeatability. Whole left ventricular and regional MBF measurements obtained using lower Rb-dose 3D PET were highly correlated over a wide range with those from 2D PET. Therefore, MBF with 3D PET can be applied using a lower Rb dosage in clinical settings with reduced radiation exposure.