Effect of variable left ventricular ejection fraction assessed by equilibrium radionuclide angiocardiography using different software packages on the diagnosis of cardiotoxicity in patients with cancer.

BACKGROUND: The equilibrium radionuclide angiocardiography (ERNA) scan is an established imaging modality for assessing left ventricular ejection fraction (LVEF) in oncology patients. This study aimed to explore the interchangeability of two commercially available software packages (MIM and JS) for LVEF measurement for a cancer-therapy-related cardiac dysfunction (CTRCD) diagnosis. METHODS: This is a single-center retrospective study among 322 patients who underwent ERNA scans. A total of 582 scans were re-processed using MIM and JS for cross-sectional and longitudinal LVEF measurements. RESULTS: The median LVEF for MIM and JS were 56% and 66%, respectively (P < 0.001). LVEF processed by JS was 9.91% higher than by MIM. In 87 patients with longitudinal ERNA scans, serial studies processed by MIM were classified as having CTRCD in a higher proportion than serial studies processed by JS (26.4% vs 11.4%, P = 0.020). There were no significant differences in intra- or inter-observer LVEF measurement variability (R = 0.99, P < 0.001). CONCLUSIONS: Software packages for processing ERNA studies are not interchangeable; thus, reports of ERNA studies should include details on the post-processing software. Serial ERNA studies should be processed on the same software when feasible to avoid discrepancies in the diagnosis and management of CTRCD.

Feasibility of Left Ventricle Ejection Fraction Calculation Using Electrocardiographically Gated SPECT Acquisition of 99m Tc-HDP Bone Scintigraphy in Cardiac Amyloidosis.

ABSTRACT: We performed bone scintigraphy in 6 patients with suspected cardiac amyloidosis. To evaluate feasibility of left ventricle function analysis, we additionally performed electrocardiographically gated SPECT acquisition. The cardiac-gated SPECT data confirmed adequate tracer uptake for automatic myocardial contour determination. LVEF estimations ranged between 24% and 54%. Comparison with LVEF estimations from prior echocardiography generally showed only small differences. In one patient, the LVEF measurements from both methods seemed discordant, probably reflecting actual LVEF worsening, which was confirmed at follow-up echocardiography. Therefore, our results may suggest that cardiac-gated SPECT acquisition at bone scintigraphy can provide meaningful estimates of LVEF.

Diagnostic value of parameters derived from planar MUGA for detecting HFpEF in coronary artery disease patients.

BACKGROUND: In recent years, heart failure with preserved ejection fraction (HFpEF) has received increasing clinical attention. To investigate the diagnostic value of diastolic function parameters derived from planar gated blood-pool imaging (MUGA) for detecting HFpEF in coronary atherosclerotic heart disease (coronary artery disease, CAD) patients. METHODS: Ninety-seven CAD patients with left ventricular ejection fraction ≥ 50% were included in the study. Based on the left ventricular end-diastolic pressure (LVEDP), the patients were divided into the HFpEF group (LVEDP ≥ 16 mmHg, 47 cases) and the normal LV diastolic function group (LVEDP < 16 mmHg, 50 cases). Diastolic function parameters obtained by planar MUGA include peak filling rate (PFR), filling fraction during the first third of diastole (1/3FF), filling rate during the first third of diastole (1/3FR), mean filling rate during diastole (MFR), and peak filling time (TPF). Echocardiographic parameters include left atrial volume index (LAVI), peak tricuspid regurgitation velocity (peak TR velocity), transmitral diastolic early peak inflow velocity (E), average early diastolic velocities of mitral annulars (average e'), average E/e' ratio. The diastolic function parameters obtained by planar MUGA were compared with those obtained by echocardiography to explore the clinical value of planar MUGA for detecting HFpEF. RESULTS: The Receiver-operating characteristic curve analysis of diastolic function parameters obtained from planar MUGA and echocardiography to detect HFpEF showed that: among the parameters examined by planar MUGA, the area under the curve (AUC) of PFR, 1/3FF, 1/3FR, MFR and TPF were 0.827, 0.662, 0.653, 0.663 and 0.809, respectively. Among the echocardiographic parameters, the AUCs for average e', average E/e' ratio, peak TR velocity, and LAVI values were 0.747, 0.706, 0.735, and 0.633. The combination of PFR and TPF showed an AUC of 0.856. PFR combined with TPF value demonstrated better predictive value than average e' (Z = 2.020, P = 0.043). CONCLUSION: Diastolic function parameters obtained by planar MUGA can be used to diagnose HFpEF in CAD patients. PFR combined with TPF was superior to the parameters obtained by echocardiography and showed good sensitivity and predictive power for detecting HFpEF.

Routine first-line detection of breast cancer therapy-related cardiotoxicity by serial, fast and ultra-low-dose equilibrium radionuclide angiography.

BACKGROUND: This study assesses a first-line left ventricular ejection fraction (LVEF) monitoring provided by an ultra-low-dose equilibrium radionuclide angiography (ERNA) in breast cancer women treated with potentially cardiotoxic drugs and analyzes patient outcome based on the ERNA results. METHODS: Breast cancer women treated with anthracyclines, followed or not by trastuzumab, were monitored using ERNA with a high-sensitivity CZT-camera. Calibrated LVEF measurements were obtained with an almost threefold reduction of radiation doses and 10-min recording times. RESULTS: During a mean 24 ± 6 months follow-up, 552 ERNAs with a mean effective dose of 2.3 ± 0.6 mSv were performed in 195 women, among whom 22 (11%) presented both ERNA criteria of cardiotoxicity (LVEF < 50% and > 10% drop from baseline; Tox + group), 35 (18%) only one criterion (Tox ± group), and 138 (71%) neither (Tox - group). This ERNA-based classification correlated with trastuzumab-anthracycline treatment (p = 0.001), prior cardiovascular disease (p = 0.018), and cardiac outcome, with a 30-month survival with no cardiotoxicity-driven drug regimen changes of 97 ± 2% in Tox -, 60 ± 13% in Tox ± and 36 ± 13% in Tox + (p < 0.001) groups. CONCLUSION: First-line detection of breast cancer therapy-related cardiotoxicity by ultra-low-dose ERNA provides consistent results, confirming the excellent cardiac outcome for the greatest majority of women with no ERNA cardiotoxicity criteria.

Beta-blockers and mechanical dyssynchrony in heart failure assessed by radionuclide ventriculography.

BACKGROUND: Radionuclide ventriculography (RNVG) can be used to quantify mechanical dyssynchrony and may be a valuable adjunct in the assessment of heart failure with reduced ejection fraction (HFrEF). The study aims to investigate the effect of beta-blockers on mechanical dyssynchrony using novel RNVG phase parameters. METHODS: A retrospective study was carried out in a group of 98 patients with HFrEF. LVEF and dyssynchrony were assessed pre and post beta-blockade. Dyssynchrony was assessed using synchrony, entropy, phase standard deviation, approximate entropy, and sample entropy from planar RNVG phase images. Subgroups split by ischemic etiology were also investigated. RESULTS: An improvement in dyssynchrony and LVEF was measured six months post beta-blockade for both ischemic and non-ischemic groups. CONCLUSIONS: A significant improvement in dyssynchrony and LVEF was measured post beta-blockade using novel measures of dyssynchrony.

Gated Tomographic Radionuclide Angiography Using 3D-Ring CZT StarGuide SPECT/CT Head-To-Head Comparison With a Cardiac-Dedicated CZT Camera: First Clinical Use and Validation.

ABSTRACT: Gated tomographic radionuclide angiography can assess and monitor left cardiac function. Dedicated cardiac CZT cameras have enabled dose reduction and quicker acquisitions. New 3D-ring CZT general purpose systems are now available. We report 50 patients who underwent a 7-minute acquisition on a cardiac-dedicated CZT camera and 9 minutes on a new 3D-ring CZT system after mean injection of 321.4 ± 55.9 MBq 99mTc-labelled human serum albumin. There was no significant difference in left ventricular volumes, and left and right ventricular ejection fractions. These preliminary results seem to validate the use of 3D-ring CZT system for LEVF and cardiac function evaluation.

Low-dose dobutamine stress gated blood pool SPECT assessment of left ventricular contractile reserve in ischemic cardiomyopathy: a feasibility study.

PURPOSE: The purpose of the present study was to evaluate the feasibility of gated blood pool single-photon emission computed tomography (GBPS) with low-dose dobutamine (LDD) stress test, performed on a single-photon emission computed tomography (SPECT) camera equipped with cadmium-zinc-telluride (CZT) solid-state detectors, in assessing of left ventricle (LV) contractile reserve in patients with ischemic cardiomyopathy (ICM). METHODS: A total of 52 patients (age 59 ± 7.2 years, 47 men and 5 women) with ICM and a control group of 10 patients without obstructive coronary artery lesion underwent GBPS and transthoracic echocardiography (TTE) at rest and during LDD stress test (5, 10, 15 µg/kg/min). The duration of each GBPS step was 5 min. Stress-induced changes in LV ejection fraction (ΔLVEF), peak ejection rate, LV volumes, and mechanical dyssynchrony (phase histogram standard deviation, phase histogram bandwidth and entropy) obtained with GBPS were estimated. RESULTS: All GBPS indices except end-diastolic volume showed significant dynamics during stress test in both groups. The majority of parameters in ICM patients showed significant changes at a dobutamine dose of 10 µg/kg/min as compared to the rest study. Seventeen percent of ICM patients, but none from the control group, showed a decrease in LVEF during stress, accompanied by a significant increase in entropy. The intra- and inter-observer reproducibility was excellent for both rest and stress studies. There was a moderate correlation (r = 0.5, p = 0.01) between GBPS and TTE, with a mean difference value of - 1.7 (95% confidence interval - 9.8; 6.4; p = 0.06) in ΔLVEF. CONCLUSION: Low-dose dobutamine stress GBPS performed with high-efficiency CZT-SPECT cameras can be performed for evaluating stress-induced changes in LV contractility and dyssynchrony with lower acquisition time. A dobutamine dose of 10 µg/kg/min can potentially suffice to detect stress-induced changes in patients with ICM during GBPS. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04508608 (August 7, 2020).

Polarity status of trigger signal during ECG-gating affects parameters of LV function in gated myocardial perfusion SPECT.

INTRODUCTION AND BACKGROUND: The polarity status is one of the important items of specifications of trigger signal from cardiac trigger monitors with two options, either positive or negative. Some systems allow the user to set the polarity of trigger signal before imaging. Efforts should be made to set the polarity status according to the recommendations provided by the manufacturers. In case of inappropriate selection, changes in computation of end-systolic and end-diastolic volumes as well as ejection fraction may occur. OBJECTIVE: To investigate the effect of the polarity status of trigger signals in synchronization process during 8- and 16-frame gated SPECT imaging on the systolic and diastolic parameters of LV function. METHODS: Thirty-four patients referred for a myocardial perfusion SPECT were consecutively included in the study. The rest scan for each patient was performed with 8- and 16-frame gating simultaneously with positive trigger signal set by the operator in a cardiac trigger monitor and then repeated after manual selection of negative polarity. In total, the 4 imaging modes acquired were 8-frame/positive-trigger, 16-frame/positive-trigger, 8-frame/negative-trigger, and 16-frame/negative-trigger. All SPECT images were reconstructed and processed with the same values of parameters. Systolic and diastolic indices of LV function were derived in QGS of the Cedars-Sinai software and then were compared using various statistical tests, and a reliability analysis was also performed. RESULTS: The age of patients recruited in the study was 58.41 ± 8.94, and 16 (47.1%) males and 18 (52.9%) females. All the correlation coefficients between corresponding parameters in positive and negative trigger signals were statistically significant. The difference between the parameters of systolic function including EF, EDV, and ESV in positive and negative trigger signals was statistically significant in paired sample t test. Likewise, a statistically significant difference was also found between mean phase angle in scans with positive and negative trigger signals by a phase difference of 147.91 (41.0% of an average cardiac cycle) and 149 (41.3% of an average cardiac cycle) degrees in 8- and 16-frame gating modes, respectively. Strong agreement (according to high values of intra-class correlation coefficient) was found for all four pairs. According to Bland-Altman results, an offset of about 3 percentage units was found, both between imaging in 8-frame gating compared to 16-frame gating, higher value in favor of 16-frame gating, and also between imaging with positive polarity trigger compared to negative-polarity trigger, again higher value in favor of positive-polarity triggering. CONCLUSION: The status of the polarity of trigger signals or similar CTM-camera delays in synchronization process during 8- and 16-frame gated SPECT imaging can be considered as one of the factors that may influence systolic and diastolic indices of LV function.

Comparison of Cadmium Zinc Telluride ECG-gated SPECT equilibrium radionuclide angiocardiography to magnetic resonance imaging to measure right ventricular volumes and ejection fraction in patients with cardiomyopathy.

AIMS: The objective of this study was to determine the accuracy of right ventricular function (RVF) assessed by Cadmium Zinc Telluride ECG-gated SPECT equilibrium radionuclide angiocardiography (CZT-ERNA). METHODS AND RESULTS: Twenty-one consecutive patients with cardiomyopathy (aged 54 ± 19 years; 62% male) were included. RV ejection fraction (EF) and volumes were analyzed by CZT-ERNA and compared with values obtained by cardiac magnetic resonance imaging (CMR). Mean values were not different between CZT-ERNA and MRI for RVEF (48.1 ± 10.4% vs 50.8 ± 10.0%; P = .23). Significant correlations (P < .0001) were observed between CZT-ERNA and MRI for RVEF, RV end-diastolic volume, and end-systolic volume (r = 0.81, r = 0.93, and r = 0.96, respectively). Bland-Altman analysis showed a mean difference (bias) between CZT-ERNA and MRI for RVEF of -2.69% (95% CI - 5.35 to - 0.42) with good agreement between the 2 techniques (limits of agreement, -14.3 to 8.99). Intraobserver and interobserver reproducibility of RVF measured by CZT-ERNA was high. CONCLUSION: CZT-ERNA provides accurate, reproducible assessment of RVF and appears as a good alternative to cardiac magnetic resonance for the evaluation of the magnitude of RVF in patients with cardiomyopathy.

Correlación de sincronía de la contracción del ventrículo izquierdo con función sisto-diastólica, masa y excentricidad en diversas afecciones cardíacas mediante un software comercial dedicado de SPECT gatillado / Gated Spect evaluation of ventricular systolic synchrony: correlation with ventricular mass and excentricity in different forms of cardiac disease

INTRODUCCIÓN: Actualmente, hay nuevas herramientas de software disponibles para medir la sincronía de la contracción intraventricular izquierda mediante SPECT de perfusión miocárdica. Esta técnica permite identificar anomalías de la conducción, apoyar la terapia de resincronización en insuficiencia cardíaca refractaria e incluso la detección precoz de isquemia. OBJETIVO: Conocer la correlación de la sincronía de contracción con otros parámetros de disfunción sisto-diastólica ventricular izquierda. MÉTODO: Estudiamos 135 pacientes remitidos para pesquisa o evaluación de enfermedad coronaria conocida mediante SPECT gatillado. La evaluación de la interpretación inicial con programas QPS/QGS® visual y cuantitativo se efectuó a 50 casos con defectos de perfusión transitoria de diversos tamaños (isquemia), 25 de tipo fijo o mixto (infarto) y 60 sin ellos (normal). Los volúmenes telesistólicos oscilaron entre 26 y 458 mL. Se excluyeron casos con arritmias, anomalías de conducción y artefactos (actividad o movimiento extracardiaco). Los SPECT se procesaron retrospectivamente utilizando el programa Emory Synctool®. Del histograma de sincronía de la contracción, el ancho de banda (BW) y la desviación estándar (SD) se correlacionaron con la fracción de eyección (FEVI), volúmenes y excentricidades sistólico / diastólico, masa ventricular izquierda, tasa máxima de llenado (PFR) y tiempo al máximo de llenado (TPFR). RESULTADOS: Los BW y SD del histograma de fase de contracción fueron mayores en el grupo con defectos fijos y mixtos en comparación con los con perfusión normal. Las correlaciones en reposo y post estrés (Spearman) entre SD y BW con FEVI, volúmenes, excentricidad y masa fueron significativas (p <0,0002) salvo TPFR que no fue significativa. CONCLUSIÓN: La sincronía de contracción intraventricular sistólica izquierda medida con SPECT se correlaciona excelentemente con los parámetros funcionales sistólicos y diastólicos, así como con masa y excentricidad en diversas condiciones y tamaños cardíacos.

INTRODUCTION: New software tools are available to measure left intraventricular contraction synchrony by myocardial perfusion SPECT. This technique allows identification of conduction abnormalities, support resynchronization therapy in refractory heart failure and even allows early detection of myocardial ischemia. OBJECTIVE: To determine the correlation of systolic synchrony with other parameters of left ventricular systolic-diastolic dysfunction. METHODS: We studied 135 patients referred for screening or known coronary artery disease evaluation by triggered SPECT. Evaluation of the initial interpretation with visual and quantitative QPS/QGS® programs was performed in 50 patients with transient perfusion defects of various sizes (ischemia), 25 of fixed or mixed type (infarction) and 60 without abnormalities. Telesystolic volumes ranged from 26 to 458 mL. Cases with arrhythmias, conduction abnormalities and artifacts (extracardiac activity or motion) were excluded. SPECT scans were retrospectively processed using the Emory Synctool® software. Histograms of systolic contraction synchrony bandwidth (BW) and standard deviation (SD) were correlated with ejection fraction (LVEF), systolic/diastolic volumes and eccentricities, left ventricular mass, peak filling rate (PFR) and time to maximum filling (TPFR). RESULTS: BW and SD of the contraction pase histogram were higher in the fixed and mixed defect group compared to studies showing normal perfusion. Spearman correlations at rest and poststress between SD and BW with LVEF, volumes, eccentricity and mass were all significant (p<0.0002) except for TPFR. CONCLUSION: Left systolic intraventricular contraction synchrony measured with SPECT presents an excellent correlation with systolic and diastolic functional parameters, as well as with mass and eccentricity in various cardiac conditions and ventricular dimensions.

Analysis of Differences in Assessment of Left Ventricular Function on Echocardiography and Nuclear Perfusion Imaging.

Two widely used methods for left ventricular (LV) ejection fraction (EF) determination, echocardiography (echo) and gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), often have wide limits of agreement. Factors influencing discrepancies between core laboratory echo and MPI LVEF determinations were examined in a large series of heart failure (HF) subjects and normal controls. 879 HF and 101 control subjects had core lab analyses of echo and MPI (mean time between procedures 7-8 days). LVEF differences were analyzed using one-way analysis of variance and Bland-Altman plots. Relationships between LVEF differences and patient characteristics and outcome endpoints (mortality and arrhythmias) were explored with logistic regression, Cox proportional hazards models, and Kaplan-Meier survival analyses. There was a systematic difference between the 2 modalities; echo LVEF was higher with more severe LV dysfunction, MPI LVEF higher when systolic function was normal. LVEF results were within ±5% in only 37% of HF and 23% of control subjects. Considering discordance around the LVEF threshold 35%, there was disagreement between the 2 methods in 305 HF subjects (35%). Male gender (odds ratio (OR) = 0.200), atrial fibrillation (OR = 2.314), higher body mass index (OR = 1.051) and lower LV end-diastolic volume (OR = 0.985) were the strongest predictors of methodologic discordance. Cardiac event rates were highest if both LVEF values were ≤35% and lowest when both LVEF values were >35%. In conclusion, substantial disagreements between LVEF results by echo and MPI are common. HF patients with LVEF ≤35% by both techniques have the highest 2-year event risk.

A comparison of 8 and 16 frames gated SPECT imaging for determination of left ventricular volumes and ejection fraction: effects of gender and myocardial counts.

In myocardial gated SPECT imaging each cardiac cycle is divided into 8 or 16 temporal frames and the cause of the difference between 8 and 16 frames is not specified exactly. The aim of this study was to investigate the effect of myocardial detector counts and gender on the difference between 8 and 16 frames and also to compare the LVEF obtained by 8 and 16 frames with echocardiography. The study population included 84 patients who underwent gated SPECT imaging. Left ventricular parameters were assessed on 8 and 16 frames gated SPECT. LVEF was also measured with two-dimensional echocardiography within 5-10 days after gated SPECT imaging. There was a good correlation between 8 and 16 frames for calculation of LVEF (p = 0.00, r = 0.860), EDV (p = 0.00, r = 0.965) and ESV (p = 0.00, r = 0.956) in all patients. But the difference between 8 and 16 frames for calculation of LVEF (p = 0.00), EDV (p = 0.014) and ESV (p = 0.00) was statistically significant. This difference was assessed separately in females, males, patients with high photon counts and patients with low photon counts and in all subgroups was statistically significant difference in the estimation of LVEF and ESV (p < 0.05) but no significant difference in the estimation of EDV (p > 0.05). Echocardiography resulted in smaller LVEF as compared to 8 and 16 frames gated SPECT studies and there was a significant difference between the two methods (p = 0.00). The myocardial detector counts and gender have no effect on the difference between 8 and 16 frames methods and the LVEF on echocardiography is smaller than the gated SPECT, but the 8-frame is closer to echocardiography.

Evaluation of left ventricular volumes and ejection fraction by 99mTc-MIBI gated SPECT and 18F-FDG gated PET in patients with prior myocardial infarction.

BACKGROUND: This study aimed to compare the accuracy of gated-SPECT (GSPECT) and gated-PET (GPET) in the assessment of left ventricular (LV) end-diastolic volumes (EDVs), end-systolic volumes (ESVs) and LV ejection fractions (LVEFs) among patients with prior myocardial infarction (MI). METHODS: One hundred and sixty-eight consecutive patients with MI who underwent GSPECT and GPET were included. Of them, 76 patients underwent CMR in addition to the two imaging modalities. The measurements of LV volumes and LVEF were performed using Quantitative Gated SPECT (QGS), Emory Cardiac Toolbox (ECTB), and 4D-MSPECT (4DM). RESULTS: The correlation between GPET, GSPECT, and CMR were excellent for LV EDV (r = 0.855 to 0.914), ESV (r = 0.852 to 0.949), and LVEF (r = 0.618 to 0.820), as calculated from QGS, ECTB, and 4DM. In addition, subgroup analysis revealed that EDV, ESV, and LVEF measured by GPET were accurate in patients with different extents of total perfusion defect (TPD), viable myocardium, and perfusion/metabolic mismatch. Furthermore, multivariate regression analysis identified that mismatch score was associated with the difference in EDV (P < 0.05) measurements between GPET and CMR. CONCLUSIONS: In patients with MI, LV volumes and LVEF scores measured by both GSPECT and GPET imaging were comparable to those determined by CMR, but should not be interchangeable in individual patients.

Left ventricle function assessment using gated first-pass 18F-FDG PET: Validation against equilibrium radionuclide angiography.

PURPOSE: We appraised the feasibility of left ventricle (LV) function assessment using gated first-pass 18F-FDG PET, and assessed the concordance of the produced measurements with equilibrium radionuclide angiography (ERNA). MATERIALS AND METHODS: Twenty-four oncologic patients benefited from 99mTc-labeled red-blood-cell ERNA, in planar mode (all patients) and using SPECT (22 patients). All patients underwent gated first-pass 18F-FDG cardiac PET. Gated dynamic PET images were reconstructed over 1 minute during tracer first-pass inside the LV and post-processed using in-house software (TomPool). After re-orientation into cardiac canonical axes and adjustment of the valves plane using a phase image, pseudo-planar PET images obtained by re-projection were automatically segmented using thresholded region growing and gradient-based delineation to produce an LV ejection fraction (EF) estimate. PET images were also post-processed in fully-tomographic mode to produce LV end diastole volume (EDV), end systole volume (ESV), and EF estimates. Concordance was assessed using Lin's concordance (ccc) and Bland-Altman analysis. Reproducibility was assessed using the coefficient of variation (CoV) and intra-class correlation (ICC). RESULTS: Pseudo-planar PET EF estimates were concordant with planar ERNA (ccc = 0.81, P < .001) with a bias of 0% (95% CI [- 2%; 3%], limits of agreement [- 11%; 12%]). Reproducibility was excellent and similar for both methods (CoV = 2 ± 1% and 3 ± 2%, P = NS; ICC = 0.97 and 0.92, for PET and ERNA, respectively). Measurements obtained in fully-tomographic mode were concordant with SPECT ERNA: ccc = 0.83 and bias = - 3 mL for LV EDV, ccc = 0.92 and bias = 0 mL for LV ESV, ccc = 0.89 and bias = - 1% for LV EF (all P values < .001 for ccc, all biases not significant). CONCLUSIONS: Gated first-pass 18F-FDG PET might stand as a relevant alternative to ERNA for LV function assessment, enabling a joint evaluation of both therapeutic response and cardiac toxicity in oncologic patients receiving cardiotoxic chemotherapy.