Assessment of Inflammation in Pulmonary Artery Hypertension by 68Ga-Mannosylated Human Serum Albumin.

Rationale: Diagnosis and monitoring of patients with pulmonary artery hypertension (PAH) is currently difficult.Objectives: We aimed to develop a noninvasive imaging modality for PAH that tracks the infiltration of macrophages into the pulmonary vasculature, using a positron emission tomography (PET) agent, 68Ga-2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) mannosylated human serum albumin (MSA), that targets the mannose receptor (MR).Methods: We induced PAH in rats by monocrotaline injection. Tissue analysis, echocardiography, and 68Ga-NOTA-MSA PET were performed weekly in rats after monocrotaline injection and in those treated with either sildenafil or macitentan. The translational potential of 68Ga-NOTA-MSA PET was explored in patients with PAH.Measurements and Main Results: Gene sets related to macrophages were significantly enriched on whole transcriptome sequencing of the lung tissue in PAH rats. Serial PET images of PAH rats demonstrated increasing uptake of 68Ga-NOTA-MSA in the lung by time that corresponded with the MR-positive macrophage recruitment observed in immunohistochemistry. In sildenafil- or macitentan-treated PAH rats, the infiltration of MR-positive macrophages by histology and the uptake of 68Ga-NOTA-MSA on PET was significantly lower than that of the PAH-only group. The pulmonary uptake of 68Ga-NOTA-MSA was significantly higher in patients with PAH than normal subjects (P = 0.009) or than those with pulmonary hypertension by left heart disease (P = 0.019) (n = 5 per group).Conclusions:68Ga-NOTA-MSA PET can help diagnose PAH and monitor the inflammatory status by imaging the degree of macrophage infiltration into the lung. These observations suggest that 68Ga-NOTA-MSA PET has the potential to be used as a novel noninvasive diagnostic and monitoring tool of PAH.

Healthcare utilization, medical expenditure, and mortality in Korean patients with pulmonary hypertension.

BACKGROUND: Limited data exists regarding healthcare utilization, medical expenses, and prognosis of pulmonary hypertension (PH) according to the World Health Organization (WHO) classification. We aimed to investigate mortality risk, healthcare utilization and medical expenditure in patients with PH across the five diagnostic subgroups. METHODS: We identified 2185 patients with PH, defined as peak tricuspid regurgitation velocity > 3.4 m/sec, among the consecutive patients referred for echocardiography between 2009 and 2015. Using diagnostic codes, medical records, and echocardiographic findings, the enrolled patients were classified according to the five subgroups by WHO classification. Healthcare utilization, costs, and all-cause mortality were assessed. RESULTS: Diagnostic subgroups of PH demonstrated significantly different clinical features. During a median of 32.4 months (interquartile range, 16.2-57.8), 749 patients (34.3%) died. Mortality risk was the lowest in group II (left heart disease) and highest in group III (chronic lung disease). The etiologies of pulmonary arterial hypertension (PAH) had significant influence on the mortality risk in group I, showing the worst prognosis in PAH associated with connective tissue disease. Medical expenditure and healthcare utilization were different between the PH subgroups: groups II and V had more hospitalizations and medical expenses than other groups. Regardless of PH subgroups, the severity of PH was associated with higher mortality risk, more healthcare utilization and medical expenditure. CONCLUSIONS: Significant differences in clinical features and prognostic profiles between PH subgroups reflect the differences in pathophysiology and clinical consequences. Our findings highlight the importance of comprehensive understanding of PH according to the etiology and its severity.

Risk of end-stage renal disease in patients with hypertrophic cardiomyopathy: A nationwide population-based cohort study.

Although hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy, has mortality rate as low as general population, previous studies have focused on identifying high-risk of sudden cardiac death. Thus, long-term systemic impact of HCM is still unclear. We sought to investigate the association between HCM and end-stage renal disease (ESRD). This was a nationwide population-based cohort study using the National Health Insurance Service database. We investigated incident ESRD during follow-up in 10,300 adult patients with HCM (age 62.1 years, male 67.3%) and 51,500 age-, sex-matched controls. During follow-up (median 2.8 years), ESRD developed in 197 subjects; 111 (1.08%) in the HCM, and 86 (0.17%) in the non-HCM (incidence rate 4.14 vs. 0.60 per 1,000 person-years, p < 0.001). In the HCM, the incidence rate for ESRD gradually increased with age, but an initial peak and subsequent plateau in age-specific risk were observed. HCM was a significant predictor for ESRD (unadjusted HR 6.90, 95% CI 5.21-9.15, p < 0.001), as comparable to hypertension and diabetes mellitus. Furthermore, after adjusting for all variables showing the association in univariate analysis, HCM itself remained a robust predictor of ESRD development (adjusted HR 3.93, 95% CI 2.82-5.46, p < 0.001). The consistent associations between HCM and ESRD were shown in almost all subgroups other than smokers and subjects with a history of stroke. Conclusively, HCM increased the risk of ESRD, regardless of known prognosticators. It provides new insight into worsening renal function in HCM, and active surveillance for renal function should be considered.

Prognostic Value of Cardiac MR Imaging for Preoperative Assessment of Patients with Severe Functional Tricuspid Regurgitation.

Purpose To explore the prognostic value of cardiac magnetic resonance (MR) imaging in predicting postoperative cardiac death in patients with severe functional tricuspid regurgitation (TR). Materials and Methods This study was approved by the institutional review board, and written informed consent was obtained from all patients. Prospectively collected data included cardiac MR images, New York Heart Association (NYHA) functional class, a comprehensive laboratory test, and clinical events over the follow-up period in 75 consecutive patients (61 women and 14 men; mean age ± standard deviation, 59 years ± 9) undergoing corrective surgery for severe functional TR. Cox proportional hazards models were used to assess the association between cardiac MR parameters and outcomes. Results During a median follow-up period of 57 months (range, 21-82 months), cardiac mortality and all-cause mortality were 17.3% and 26.7%, respectively, with a surgical mortality of 6.7%. Cardiac death risk was lower with a higher right ventricular (RV) ejection fraction (EF) on cardiac MR images (hazard ratio per 5% higher EF = 0.790, P = .048). By adjusting for confounding variables, RV EF remained a significant predictor for cardiac death (P < .05) and major postoperative cardiac events (P < .05). The area under the receiver operating characteristic curve (AUC) confirmed the incremental role of RV EF on cardiac MR images in the prediction of postoperative cardiac death (AUC, 0.681-0.771; P = .041) and major postoperative cardiac events (AUC, 0.660-0.745; P = .044) on top of NYHA class. RV end-systolic volume index was also independently associated with these outcomes but failed to increase the AUC significantly. Conclusion Preoperative assessment of cardiac MR imaging-based RV EF provides independent and incremental prognostic information in patients undergoing corrective surgery for severe functional TR. (©) RSNA, 2016 Online supplemental material is available for this article.

Visual Assessment of Relative Apical Sparing Pattern Is More Useful Than Quantitative Assessment for Diagnosing Cardiac Amyloidosis in Borderline or Mildly Increased Left Ventricular Wall Thickness.

BACKGROUND: Relative apical sparing pattern of longitudinal strain (RapSP-LS) was suggested in advanced cardiac amyloidosis (CA). It is unclear whether it is present in less advanced CA. METHODS AND RESULTS: Patients with presumptive diagnosis of CA and mean left ventricular wall thickness (LVWT) ≤14 mm were recruited. Apart from RapSP-LS visually identified, relative apical longitudinal strain index (RapLSI) was defined as [average apical LS/(average basal LS+average mid-ventricle LS)]. Among 119 patients included, 47 were finally diagnosed with CA. RapLSI was higher in the CA group compared to other causes of increased mean LVWT (P<0.001), but with a significant range of overlap noted. In contrast, RapSP-LS visually assessed was noted in most CA patients (31/47, 66.0%) except in those with preserved LV ejection fraction, normal LVWT, and mildly decreased global LS, suggesting least advanced CA. On multivariate analysis of the added diagnostic role of RapSP-LS or RapLSI on top of clinical, electrocardiographic, and conventional echocardiographic parameters, addition of RapLSI produced only borderline increase in area under the curve of the multivariate model (P=0.05), whereas addition of RapSP-LS significantly increased it (P<0.001). CONCLUSIONS: Visual identification of RapSP-LS is useful in terms of added diagnostic value compared with quantitative calculation of RapLSI. Its clinical application, however, should be used with caution in patients with less advanced CA.

Assessment of diffuse myocardial fibrosis by using MR imaging in asymptomatic patients with aortic stenosis.

PURPOSE: To assess whether native T1 mapping provides noninvasive estimation of diffuse myocardial fibrosis and whether it correlates with subclinical myocardial dysfunction in asymptomatic patients with aortic stenosis (AS). MATERIALS AND METHODS: The local institutional review board approved the study, and all patients gave informed consent. Eighty asymptomatic patients with moderate or severe AS and normal left ventricular (LV) ejection fraction (mean age, 67 years; range, 31-81 years) and 15 sex-matched control subjects (mean age, 33 years; range, 23-41 years) were prospectively enrolled. Patients underwent two-dimensional echocardiography, speckle tracking imaging, and cardiac 3.0-T magnetic resonance (MR) imaging, including mapping of T1 relaxation time by using the modified Look-Locker inversion-recovery sequence. Correlations between native T1 values and the degree of diffuse fibrosis in myocardial specimens obtained during aortic valve replacement surgery were analyzed in a subset of 20 patients. Correlations between parameters of myocardial function and structure and native T1 values were assessed with Pearson correlation coefficients. RESULTS: Native T1 values correlated well with the degree of diffuse myocardial fibrosis in intraoperative myocardial biopsy specimens (r = 0.777, P < .001) and differed significantly between patients with AS and control subjects (1208 msec ± 45 vs 1169 msec ± 21, P < .001). LV volumes and mass differed significantly according to AS groups, categorized by T1 tertiles (all P < .001), as well as degree of AS severity (0.55 cm(2)/m(2) ± 0.14 for lowest native T1 tertile, 0.46 cm(2)/m(2) ± 0.12 for middle native T1 tertile, and 0.45 cm(2)/m(2) ± 0.13 for highest native T1 tertile [P = .008] for indexed aortic valve area at echocardiography). Native T1 correlated significantly with global longitudinal strain measured with two-dimensional speckle tracking imaging (r = 0.598, P < .001), e' velocity (r = -0.437, P < .001), and indexed left atrial volume (r = 0.475, P < .001). CONCLUSION: Native T1 mapping provides a noninvasive estimation of diffuse myocardial fibrosis and correlates with subclinical myocardial dysfunction in asymptomatic patients with AS.

Assessment of left ventricular mass in hypertrophic cardiomyopathy by real-time three-dimensional echocardiography using single-beat capture image.

BACKGROUND: Left ventricular (LV) mass is an important prognostic indicator in hypertrophic cardiomyopathy. Although LV mass can be easily calculated using conventional echocardiography, it is based on geometric assumptions and has inherent limitations in asymmetric left ventricles. Real-time three-dimensional echocardiographic (RT3DE) imaging with single-beat capture provides an opportunity for the accurate estimation of LV mass. The aim of this study was to validate this new technique for LV mass measurement in patients with hypertrophic cardiomyopathy. METHODS: Sixty-nine patients with adequate two-dimensional (2D) and three-dimensional echocardiographic image quality underwent cardiac magnetic resonance (CMR) imaging and echocardiography on the same day. Real-time three-dimensional echocardiographic images were acquired using an Acuson SC2000 system, and CMR-determined LV mass was considered the reference standard. Left ventricular mass was derived using the formula of the American Society of Echocardiography (M-mode mass), the 2D-based truncated ellipsoid method (2D mass), and the RT3DE technique (RT3DE mass). RESULTS: The mean time for RT3DE analysis was 5.85 ± 1.81 min. Intraclass correlation analysis showed a close relationship between RT3DE and CMR LV mass (r = 0.86, P < .0001). However, LV mass by the M-mode or 2D technique showed a smaller intraclass correlation coefficient compared with CMR-determined mass (r = 0.48, P = .01, and r = 0.71, P < .001, respectively). Bland-Altman analysis showed reasonable limits of agreement between LV mass by RT3DE imaging and by CMR, with a smaller positive bias (19.5 g [9.1%]) compared with that by the M-mode and 2D methods (-35.1 g [-20.2%] and 30.6 g [17.6%], respectively). CONCLUSIONS: RT3DE measurement of LV mass using the single-beat capture technique is practical and more accurate than 2D or M-mode LV mass in patients with hypertrophic cardiomyopathy.

Impact of afterload on the assessment of severity of aortic stenosis.

BACKGROUND: Aortic stenosis (AS) is increasingly diagnosed in current aging society. Echocardiography is the most important tool in the assessment of AS and its severity. However, load-dependency of Doppler measurement could affect the accuracy of AS severity assessment. We tried to evaluate the impact of afterload on the assessment of AS severity by modification of afterload using pneumatic compression (Pcom). METHODS: Forty patients diagnosed as moderate or severe AS [effective orifice area of aortic valve (EOA(AV)) by continuity equation of < 1.5 cm(2)] were consecutively enrolled. Patients with severely uncontrolled hypertension, severe left ventricular (LV) dysfunction, and other significant valve disease were excluded. Comprehensive echocardiography was performed at baseline to assess AS severity. Then, pneumatic compression of the lower extremities by 100 mmHg was applied to increase LV afterload. After 3 minutes, echocardiography was repeated to assess AS severity. RESULTS: Mean blood pressure was significantly increased under Pcom (p < 0.001), while heart rate remained unchanged. Peak aortic valve velocity (V(max)) was slightly, but significantly decreased under Pcom (p = 0.03). However, Doppler velocity index and EOA(AV) by continuity equation were not affected by Pcom. CONCLUSION: AS severity assessment by echocardiography was not dependent on the change of LV afterload imposed by Pcom. AV V(max) was slightly decreased with LV afterload increment, but these changes were too small to alter treatment plan of AS patients. EOA(AV) and Doppler velocity index are more stable parameters for AS severity assessment.

Load independence of two-dimensional speckle-tracking-derived left ventricular twist and apex-to-base rotation delay in nonischemic dilated cardiomyopathy: implications for left ventricular dyssynchrony assessment.

BACKGROUND: Left ventricular (LV) twist mechanics are a promising, sensitive tool for assessing pathophysiologic changes in patients with systolic heart failure. Although LV twist is known to be load dependent in healthy volunteers, this has not been examined in patients with "long-standing" dilated cardiomyopathy (DCM). The aim of this study was to determine whether LV twist remains load dependent in the setting of long-standing, nonischemic DCM. METHODS: Thirty-four patients with DCM with baseline LV ejection fractions (LVEFs) < 40% and 13 subjects with preserved LVEFs (≥50%) were enrolled. After baseline measurements, pneumatic compression of the lower extremities (Pcom) was used to increase LV afterload. Subsequently, sublingual nitroglycerin (SL-NG) was administered to modify preload. Conventional echocardiographic parameters, LV end-systolic wall stress, net LV twist angle, and apex-to-base-rotation delay (ABRD) were assessed under each condition. RESULTS: In patients with DCM, although LV end-systolic wall stress significantly increased under Pcom (196.9 ± 64.9 g/m(2) at baseline vs 231.8 ± 78.9 g/m(2) under Pcom, P < .017) and decreased after SL-NG application (231.8 ± 78.9 g/m(2) under Pcom vs 197.4 ± 67.4 g/m(2) after SL-NG, P < .017), net LV twist angle and ABRD showed no significant changes depending on LV loading condition (for LV twist, 7.63 ± 4.47° at baseline vs 7.03 ± 4.13° under Pcom vs 7.35 ± 4.36° after SL-NG, P = 0.65; for ABRD, 16.56 ± 13.81% at baseline vs 17.19 ± 14.81% under Pcom vs 15.95 ± 13.27% after SL-NG, P = .53). Careful examination of individual patient data revealed that LV twist was load independent when patients had LV twist < 12°. ABRD was also found to be load independent, but only in patients with LVEFs < 34%. In contrast, LV twist and ABRD were load dependent in patients with preserved LVEFs. CONCLUSIONS: LV twist and its component, ABRD, had relatively load insensitive properties in patients with long-standing DCM and can be used in future clinical trials as load-independent indexes of LV dyssynchrony.

Importance of clinical and echocardiographic hemodynamic assessment in chronic pulmonary embolism.

We describe a 42-year-old man presenting to the emergency department with cardiogenic shock. He had a prior history of acute pulmonary embolism (PE), and had been on anticoagulation for 2 years. Although computed tomographic pulmonary angiography performed at the emergency department showed no change in the extent of PE and did not support a role of surgical treatment, pulmonary embolectomy was recommended by attending physician based on clinical and echocardiographic hemodynamic findings like unstable vital sign and markedly enlarged right ventricle with severely depressed systolic function. Surgery confirmed the presence of fresh thrombi. After surgery, hemodynamic status was progressively improved, but the patient died due to pneumonia and pulmonary hemorrhage.

Assessment of haemodynamic effects of surgical correction for severe functional tricuspid regurgitation: cardiac magnetic resonance imaging study.

AIMS: There has been growing attention for the development of functional tricuspid regurgitation (TR) long after left-sided valve surgery. We attempted to determine the long-term haemodynamic effects of corrective surgery for severe functional TR in patients who had prior left-sided valve surgery using cardiac magnetic resonance imaging (CMR). METHODS AND RESULTS: Thirty-one patients with severe functional TR (TR fraction of 46.0+/-16.2% by CMR) were analysed. CMR was performed within 1 month before and at a median 27.0 months after surgery. Long after TR surgery, 28 of the 31 patients had no or mild residual TR, two had mild-to-moderate TR, and one showed moderate TR. Remarkable reductions in the right ventricular (RV) end-diastolic volume index (RV-EDVI) (177.4+/-59.1 mL/m(2) vs. 118.2+/-31.2 mL/m(2), P<0.001) and end-systolic volume index (RV-ESVI) (88.5+/-30.1 mL/m(2) vs. 67.2+/-31.0 mL/m(2), P=0.002) were observed, whereas RV ejection fraction (RV-EF) showed no change (49.7+/-8.3% vs. 44.9+/-12.5%, P=0.09). Pre-operative RV-EDVI (R=-0.86, P<0.001) and RV-ESVI (R=-0.55, P=0.001) were significantly associated with their respective changes after corrective surgery. Post-surgery, a normal RV-EF was achieved in 14 patients (42.5%). Pre-operative RV-EDVI of 164 mL/m(2) effectively discriminated patients with normal RV-EF from those without post-surgery, with a sensitivity of 77% and a specificity of 72% (P=0.01). A significant rise in the left ventricular (LV) EDVI and cardiac index (CI) was found after surgery (from 92.9+/-24.4 to 123.2+/-31.6 mL/m(2) for LV-EDVI, P<0.001; from 3.8+/-1.3 to 4.2+/-0.8 L/min/m(2) for CI, P=0.03). Functional capacity as assessed by NYHA class showed a significant improvement from 2.7+/-0.6 before surgery to 2.0+/-0.6 long after surgery (P<0.001). CONCLUSION: Successful TR surgery can remarkably reduce RV volumes and preserve RV systolic function. In addition, successful TR surgery led to a significant rise in LV preload and CI, which may significantly contribute to a significant amelioration in the functional capacity of the patients. It seems that RV volume measurement by CMR is helpful for determining optimal timing for TR surgery.

Persistent regional diastolic dysfunction after myocardial ischemia and the effect of statin treatment: assessment with two-dimensional radial strain rate.

BACKGROUND: Persistence of regional diastolic dysfunction after ischemic insult remains debatable. With speckle tracking echocardiography (STE), we sought to (1) prove the persistence of regional diastolic dysfunction, (2) assess the feasibility of applying persistent regional diastolic dysfunction to differentiating ischemic and nonischemic chest pain, and finally (3) examine statin effects on postischemic regional diastolic dysfunction. METHODS: Nineteen patients with variant angina (VA) and 12 normal subjects were enrolled. Comprehensive echocardiographic examinations were performed before and 1 day after coronary angiography (CAG) with ergonovine provocation. Radial systolic (rSRsys) and diastolic (rSRdia) strain rates were obtained and averaged using standard segmentation models corresponding to the three major coronary territories assigned. RESULTS: No significant changes in rSRsys and rSRdia values were observed for controls and in rSRsys for VA. However, rSRdia for VA demonstrated a weak, but significant, decrease from -2.25 +/- 0.71/sec to -2.04 +/- 0.71/sec (P = 0.003) 1 day after CAG. However, because of the wide overlap between rSRdia values in normal and ischemic segments for VA patients, predictability of remote ischemia based solely on the rSRdia was limited. Subgroup analysis according to statin prescription showed that statin administration contributed to the elimination of rSRdia reduction (-2.28 +/- 0.84/sec on pre-CAG vs. -2.29 +/- 0.77/sec on post-CAG, P = 0.72 for patients without statin premedication; -2.23 +/- 0.64/sec for pre-CAG vs. -1.88 +/- 0.65/sec for post-CAG, P = 0.002 for those without). Expectedly, rSRsys values showed no significant changes in all situations. CONCLUSIONS: The presence and sustained nature of regional diastolic dysfunction can be demonstrated with STE. Statin minimized the persistence of regional diastolic dysfunction after an acute ischemia. Although the clinical usefulness of rSRdia by STE appears to be limited, its clinical utility requires further consideration, given the brevity of the ischemia provoked during CAG with ergonovine and the protracted regional diastolic dysfunction.

Assessment of left ventricular rotation and torsion with two-dimensional speckle tracking echocardiography.

BACKGROUND: Speckle tracking echocardiography (STE) has a unique feature of angle independence and, thus, may provide a powerful means of assessing left ventricular (LV) torsion (LVtor). The aims of this study were to assess: (1) the feasibility of 2-dimensional STE in the measurement of LVtor; and (2) the relationship of LVtor with age and conventional echocardiographic parameters. METHODS: We consecutively recruited 160 healthy volunteers. After obtaining conventional echocardiographic parameters, apical and basal short-axis rotations were assessed with STE. LVtor was defined as the net difference between rotation angles in the two short-axis planes normalized for LV longitudinal length. RESULTS: Reliable LVtor measurement was possible only in 56 volunteers (35%). This low feasibility was largely a result of the failure to obtain reliable basal rotation values. In 56 volunteers who were finally enrolled in this study, a significant correlation was found between LV ejection fraction and LVtor (r = 0.56, P < .001) and this correlation was attributed to apical (r = 0.47, P < .001) but not basal (P = .14) rotation. There was no significant change in LVtor with aging. However, initial counterclockwise motion (r = -0.51, P = .001) and its interval (r = -0.44, P = .001) in the basal rotation gradually decreased with aging, and correlated with early transmitral inflow velocity (r = 0.44 and 0.49, respectively) and its deceleration time (r = -0.43 and -0.48, respectively) (all P < .001). In contrast, such correlations were not found for initial clockwise motion and its interval in the apical rotation. CONCLUSIONS: Currently, STE has limited feasibility in the measurement of LVtor. There was no significant age-related change in LVtor. In LV rotations, basal rotation was affected by the age-related changes in the LV early diastolic filling, whereas apical rotation was mainly related to LV systolic performance.

Assessment of coronary vasodilatation in response to nitroglycerin with transthoracic Doppler echocardiography.

BACKGROUND: Previous studies demonstrated impaired coronary vasodilatory response (VR) to nitroglycerin (NG) in patients with coronary atherosclerosis. We hypothesized that the effect of the NG on the coronary blood flow (CBF) is negligible compared with its effect on the epicardial coronary artery dilatation and, therefore, that CBF velocity reduction after NG can reflect the magnitude of epicardial coronary artery dilatation. METHODS: Quantitative coronary angiography was performed at the left anterior descending coronary artery (LAD) before and after intracoronary NG (200 mug) infusion in 18 patients with normal-looking coronary angiogram. VR assessed by quantitative coronary angiography (VRangio) was defined as: (LAD diameter after NG)(2)/(LAD diameter before NG)(2). Mean values measured at the ostium and at the junction of mid and distal LAD were used in the analysis. Diastolic CBF velocity was evaluated by using a 7-MHz transducer at the distal LAD before and 3 minutes after sublingual NG. VR assessed by echocardiography (VRecho) was defined as: (mean diastolic CBF velocity before sublingual NG)/(mean diastolic CBF velocity after sublingual NG). In 11 patients, plaque burden was assessed by intravascular ultrasound and results were compared with VRangio and VRecho. RESULTS: VRecho was found to correlate well with VRangio (r = 0.71, P = .001), and VRangio and VRecho showed significant negative correlations with plaque burden (r = -0.66, P = .03; r = -0.77, P = .005, respectively). CONCLUSIONS: VR to NG can be evaluated noninvasively with transthoracic Doppler echocardiography.