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.

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.

18F-FDG uptake of the right ventricle is an important predictor of histopathologic diagnosis by endomyocardial biopsy in patients with cardiac sarcoidosis.

BACKGROUND: The aim of this study was to determine whether right ventricle (RV) 18F-fluorodeoxyglucose (FDG) uptake can predict positive findings of endomyocardial biopsy (EMB) in patients with cardiac sarcoidosis (CS). METHODS: 70 consecutive patients with clinically diagnosed CS who had undergone FDG PET were registered in the present study. Patients without EMB (n = 42) were excluded. Ultimately, 28 patients were studied. EMB samples were obtained from the RV septum. We evaluated the FDG uptake on six segments (RV, left ventricle anterior, septal, lateral, inferior, and apex). RESULTS: Positive EMB was found in six patients (21%). Patients were divided into two groups according to positive (n = 12 [43%]) or negative (n = 16 [57%]) RV FDG uptake. Patients with positive RV FDG uptake had a significantly higher frequency of positive EMB than those without (42% vs. 6%, P = 0.024). On the other hand, there was no EMB-predictive value for the FDG uptakes in the other five segments, the cardiac metabolic volume, total lesion glycolysis, left ventricular ejection fraction, or any electrocardiogram findings. CONCLUSIONS: FDG uptake of the RV but no other heart segment was associated with positive EMB in CS patients. The presence of RV FDG uptake could improve the rate of positive EMB up to 42% in patients with CS.

Use of 18F-FDG PET/CT texture analysis to diagnose cardiac sarcoidosis.

PURPOSE: 18F-fluorodeoxyglocose positron emission tomography (FDG PET) plays a significant role in the diagnosis of cardiac sarcoidosis (CS). Texture analysis is a group of computational methods for evaluating the inhomogeneity among adjacent pixels or voxels. We investigated whether texture analysis applied to myocardial FDG uptake has diagnostic value in patients with CS. METHODS: Thirty-seven CS patients (CS group), and 52 patients who underwent FDG PET/CT to detect malignant tumors with any FDG cardiac uptake (non-CS group) were studied. A total of 36 texture features from the histogram, gray-level co-occurrence matrix (GLCM), gray-level run length matrix (GLRLM), gray-level zone size matrix (GLZSM) and neighborhood gray-level difference matrix (NGLDM), were computed using polar map images. First, the inter-operator and inter-scan reproducibility of the texture features of the CS group were evaluated. Then, texture features of the patients with CS were compared to those without CS lesions. RESULTS: Twenty-eight of the 36 texture features showed high inter-operator reproducibility with intraclass correlation coefficients (ICCs) over 0.80. In addition, 17 of the 36 showed high inter-scan reproducibility with ICCs over 0.80. The SUVmax showed no difference between the CS and non-CS group [7.36 ± 2.77 vs. 8.78 ± 4.65, p = 0.45, area under the curve (AUC) = 0.60]. By contrast, 16 of the 36 texture features could distinguish CS from non-CS grsoup with AUC > 0.80. Multivariate logistic regression analysis after hierarchical clustering concluded that long-run emphasis (LRE; P = 0.0004) and short-run low gray-level emphasis (SRLGE; P = 0.016) were significant independent factors that could distinguish between the CS and non-CS groups. Specifically, LRE was significantly higher in CS than in non-CS (30.1 ± 25.4 vs. 11.4 ± 4.6, P < 0.0001), with high diagnostic ability (AUC = 0.91), and had high inter-operator reproducibility (ICC = 0.98). CONCLUSIONS: The texture analysis had high inter-operator and high inter-scan reproducibility. Some of texture features showed higher diagnostic value than SUVmax for CS diagnosis. Therefore, texture analysis may have a role in semi-automated systems for diagnosing CS.

The role of multimodality imaging in takotsubo cardiomyopathy.

Takotsubo cardiomyopathy (TC) is a syndrome of transient left ventricular (LV) dysfunction mimicking acute coronary syndrome. Although the mechanisms underlying the occurrence of TC are unknown, several imaging techniques contribute to its diagnosis. Here we review the current knowledge about TC, in particular, the pathophysiology and the role of imaging including nuclear cardiovascular medicine.

Progressive left ventricular dysfunction and myocardial fibrosis in Duchenne and Becker muscular dystrophy: a longitudinal cardiovascular magnetic resonance study.

This study examined the progression of left ventricular dysfunction and myocardial fibrosis in patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) to evaluate the effects of angiotensin-converting enzyme inhibitor (ACEI). Ninety-eight cardiovascular magnetic resonance (CMR) studies in 34 consecutive patients with DMD (n = 21) or BMD (n = 13) were retrospectively reviewed. Left ventricular ejection fraction (LVEF) and the extent of myocardial late gadolinium enhancement (LGE) were semiautomatically quantified. During the study period, five patients had already been treated with ACEI at the first CMR; five were started on ACEI at LVEF ≥ 55% and 10 at LVEF < 55%. All patients had hyperenhanced myocardium on LGE images at the first CMR (median extent, 3.3%; interquartile range 0.1-14.3%). A mixed-effects model for longitudinal data of each patient, adjusted for age, type of muscular dystrophy, steroid use, and ACEI use showed that higher age (ß = - 1.1%/year; 95% confidence interval [CI], - 1.8% to - 0.4%; p = 0.005) and no use of ACEI (ß = - 3.1%; 95% CI, - 5.4% to - 0.8%; p = 0.009) were significantly associated with a lower LVEF. When ACEI use was stratified by time of initiation (LVEF ≥ 55% vs. < 55%), only ACEI initiation at LVEF < 55% had a beneficial effect on LVEF at each imaging examination (ß = 3.7%; 95% CI, 0.9-6.4%; p = 0.010). ACEI use or the time of initiation of ACEI did not significantly affect age-related increase in LGE. ACEI attenuated the age-related decline in LVEF only in patients with DMD or BMD and reduced LVEF, suggesting that further investigation on prophylactic use of cardioprotective therapy in these patients is warranted.

The role of nuclear medicine in assessments of cardiac dyssynchrony.

Radionuclide imaging has an advantage for quantitative analyses of the tracer concentration and its temporal changes. Myocardial perfusion and function have been adapted for synchrony analyses. Extracted parameters have been demonstrated to measure ventricular synchrony and even to predict CRT outcomes. ERNA has the advantages of higher temporal resolution, greater reproducibility, and the volumetric analysis of both ventricles that can be applied for analyses of intraventricular synchrony and interventricular synchrony. Several software packages such as Quantitative Gated SPECT, the Emory Cardiac Toolbox, cardioREPO, and Heart Function View are available to assess the LV dyssynchrony parameters from GSPECT. A count-based method is applied to extract the amplitude and phase from each of the reconstructed GSPECT short-axis datasets throughout the cardiac cycle and then subjected to a Fourier analysis, the results of which are displayed on a polar map and histogram. Some of the parameters such as the bandwidth (expressed as the 95% width of the phase histogram) and the standard deviation of the phase are obtained by the phase histogram to assess the intraventricular synchrony. This review paper focuses on the application of the LV dyssynchrony parameters estimated by cardiac SPECT in patients with a heart disease.

Correction to: The role of nuclear medicine in assessments of cardiac dyssynchrony.

Some of the values in Table 3 of the original publication inadvertently contained discrepancies with the literature from which they were taken. A corrected version of Table 3 can be found below; the values which have been corrected now appear in bold text (row: Romero-Farina G).

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.

Myocardial T1-mapping and Extracellular Volume Quantification in Patients and Putative Carriers of Muscular Dystrophy: Early Experience.

To assess myocardial fibrosis associated with muscular dystrophy, T1-mapping and extracellular volume fraction (ECV) quantification was prospectively performed using cardiovascular MR (CMR) imaging in 6 male patients with muscular dystrophy and 5 female putative carriers of Duchenne or Becker muscular dystrophy. Five patients and all putative carriers had an elevated ECV (>29.5% for men and >35.2% for women), suggesting that ECV has a potential to detect diffuse fibrotic changes in patients and putative carriers of muscular dystrophy.

Improved regional myocardial blood flow and flow reserve after coronary revascularization as assessed by serial 15O-water positron emission tomography/computed tomography.

AIMS: Myocardial perfusion imaging without and with quantitative myocardial blood flow (MBF) and myocardial flow reserve (MFR) plays an important role in the diagnosis and risk stratification of patients with stable coronary artery disease (CAD). We aimed to quantify the effects of coronary revascularization on regional stress MBF and MFR and to determine whether the presence of subendocardial infarction was associated with these changes. METHODS AND RESULTS: Forty-seven patients with stable CAD were prospectively enrolled. They underwent 15O-water positron emission tomography at baseline and 6 months after optimal medical therapy alone (n = 16), percutaneous coronary intervention (PCI) (n = 18), or coronary artery bypass grafting (CABG) (n = 13). Stenosis of ≥50% diameter was detected in 98/141 vessels (70%). The regional MFR was significantly increased from baseline to follow-up [1.84 (interquartile range, IQR 1.28-2.17) vs. 2.12 (IQR 1.69-2.63), P < 0.001] in vessel territories following PCI or CABG due to an increase in the stress MBF [1.33 (IQR 0.97-1.67) mL/g/min vs. 1.64 (IQR 1.38-2.17) mL/g/min, P < 0.001], whereas there was no significant change in the regional stress MBF or MFR in vessel territories without revascularization. A multilevel mixed-effects models adjusted for baseline characteristics, subendocardial infarction assessed by cardiovascular magnetic resonance imaging, and intra-patient correlation showed that the degree of angiographic improvement after coronary revascularization was significantly associated with increased regional stress MBF and MFR (P < 0.05 for all). CONCLUSION: Coronary revascularization improved the regional stress MBF and MFR in patients with stable CAD. The magnitude of these changes was associated with the extent of revascularization independent of subendocardial infarction.

Lower left ventricular ejection fraction and higher serum angiotensin-converting enzyme activity are associated with histopathological diagnosis by endomyocardial biopsy in patients with cardiac sarcoidosis.

BACKGROUND: The histopathological diagnosis of cardiac sarcoidosis (CS) is challenging because of sampling error in endomyocardial biopsy (EMB) and the determinants of positive EMB are unclear. Reduced left ventricular ejection fraction (LVEF) is a simple parameter of the extent of myocardial damage, and higher serum angiotensin-converting enzyme (ACE) activity would indicate the spread of disease activity in CS patients. Thus, we sought to examine whether these parameters are related to the histopathological diagnosis of CS by EMB. METHODS: A total of 94 consecutive clinically diagnosed CS patients between August 1986 and March 2019 who were admitted to two academic hospitals were examined. We determined EMB as positive if non-caseating epithelioid granulomas were confirmed in the myocardial tissue. Patients were divided into two groups according to positive (n = 37) and negative (n = 57) EMB. We assessed the relationship between LVEF, serum ACE activity and positive EMB. RESULTS: Multivariable analysis revealed that both LVEF and serum ACE were independently associated with positive EMB (OR 0.83, 95% CI 0.70-0.99; OR 1.39, 95% CI 1.02-1.90, respectively). Moreover, patients with both lower LVEF (<37%, median) and higher ACE activity (≥13.5 IU/L, median) had the highest frequency of positive EMB (p = .003). The combination of lower LVEF and higher serum ACE showed better specificity (91.2%) and positive predictive value (73.7%) than either LVEF or serum ACE alone for positive EMB. CONCLUSIONS: Lower LVEF and higher serum ACE activity were associated with positive EMB, suggesting that these parameters might be useful for predicting positive EMB in CS patients.

Effects of coronary revascularization on global coronary flow reserve in stable coronary artery disease.

Aims: Coronary flow reserve (CFR) is an integrated measure of the entire coronary vasculature, and is a powerful prognostic marker in coronary artery disease (CAD). The extent to which coronary revascularization can improve CFR is unclear. This study aimed to evaluate the impact of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) on CFR in patients with stable CAD. Methods and results: In a prospective, multicentre observational study, CFR was measured by 15O-water positron emission tomography as the ratio of stress to rest myocardial blood flow at baseline and 6 months after optimal medical therapy (OMT) alone, PCI, or CABG. Changes in the SYNTAX and Leaman scores were angiographically evaluated as indicators of completeness of revascularization. Follow-up was completed by 75 (25 OMT alone, 28 PCI, and 22 CABG) out of 82 patients. The median SYNTAX and Leaman scores, and baseline CFR were 14.5 [interquartile range (IQR): 8-24.5], 5.5 (IQR: 2.5-12.5), and 1.94 (IQR: 1.67-2.66), respectively. Baseline CFR was negatively correlated with the SYNTAX (ρ = -0.40, P < 0.001) and Leaman scores (ρ = -0.33, P = 0.004). Overall, only CABG was associated with a significant increase in CFR [1.67 (IQR: 1.14-1.96) vs. 1.98 (IQR: 1.60-2.39), P < 0.001]. Among patients with CFR <2.0 (n = 41), CFR significantly increased in the PCI [1.70 (IQR: 1.42-1.79) vs. 2.21 (IQR: 1.78-2.49), P = 0.002, P < 0.001 for interaction between time and CFR] and CABG groups [1.28 (IQR: 1.13-1.80) vs. 1.86 (IQR: 1.57-2.22), P < 0.001]. The reduction in SYNTAX or Leaman scores after PCI or CABG was independently associated with the percent increase in CFR after adjusting for baseline characteristics (P = 0.012 and P = 0.011, respectively). Conclusion: Coronary revascularization ameliorated reduced CFR in patients with obstructive CAD. The degree of improvement in angiographic CAD burden by revascularization was correlated with magnitude of improvement in CFR.

Which is the proper reference tissue for measuring the change in FDG PET metabolic volume of cardiac sarcoidosis before and after steroid therapy?

BACKGROUND: Cardiac sarcoidosis (CS) is a rare but potentially life-threatening disease that causes conduction disturbance, systolic dysfunction, and, most notably, sudden cardiac death. 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) plays important roles not only in diagnosing CS but also in evaluating the effects of anti-inflammatory therapy. A volume-based analysis of parameters measured by FDG PET, so-called cardiac metabolic volume (CMV), has emerged as a new assessment tool. CMV is measured as the volume within the boundary determined by a reference tissue such as the liver and the blood pool uptake. However, there is a possibility that oral steroid therapy could lead to variations of the liver and the blood pool uptake. Here, we attempted to evaluate the steroid effects on the liver and the blood pool uptake. A total of 38 CS patients who underwent FDG PET/CT before and during steroid therapy were retrospectively enrolled. Volumes of interest (VOIs) were placed in the right lobe of the liver and descending aorta (DA). The maximum standardized uptake value (SUVmax), SUVmean, and SUVpeak of the liver and DA were compared between time points before and during steroid therapy. RESULTS: The SUVmax, SUVmean, and SUVpeak of the liver during steroid therapy significantly increased from the time point before the therapy (SUVmax 3.5 ± 0.4 vs. 3.8 ± 0.6, p = 0.014; SUVmean 2.7 ± 0.3 vs. 3.0 ± 0.5, p = 0.0065; SUVpeak 3.0 ± 0.4 vs. 3.4 ± 0.6, p = 0.006). However, the SUVmax, SUVmean, and SUVpeak in the DA did not significantly change (SUVmax 2.2 ± 0.3 vs. 2.2 ± 0.4, p = 0.46; SUVmean 1.9 ± 0.3 vs. 2.0 ± 0.4, p = 0.56; SUVpeak 2.0 ± 0.3 vs. 2.0 ± 0.3, p = 0.70). CONCLUSIONS: We measured FDG uptake in the liver and blood pool before and during steroid therapy. Steroid therapy increased the liver uptake but not the blood pool uptake. Our findings suggested that the DA uptake is a more suitable threshold than liver uptake to evaluate therapeutic effects using volume-based analysis of cardiac FDG PET.