Non-apical Hypertrophic Cardiomyopathy Research Articles

Clinical utility of electrocardiographic voltage parameters for the diagnosis of hypertrophic cardiomyopathy.

While electrocardiographic parameters of hypertensive left ventricular hypertrophy (H-LVH) are well known, limited data are available regarding hypertrophic cardiomyopathy (HCM). This study was to assess the diagnostic value of electrocardiographic voltage parameters in HCM. Included patients with HCM treated between March 2015 and May 2023. Voltage parameters (S-L, Cornell, Cornell product, Lewis, Peguero, and modified Cornell voltages) and echocardiography were evaluated. Receiver operating characteristic (ROC) curves were used to assess the diagnostic value of electrocardiogram in HCM. The multiple linear regression was conducted to analyze the correlation between electrocardiogram indicators and cardiac diastolic function. The highest sensitivity for HCM was Peguero voltage (70.4%; 88.6% specificity). The Peguero voltage had high sensitivity in male (63.8%) and female patients (84.9%), those aged <65 years (71.6%) and ≥65 years (68.3%), with non-apical HCM (AHCM) (76.7%), obstructive HCM (82.1%), and non-obstructive HCM (66.9%). The sensitivity of the S-L voltage was high in AHCM (72.2%). The sensitivity for HCM reached 88.7% when the S-L and Peguero voltages were combined. The modified Cornell index had the highest area under the curve (0.88, 95% CI: 0.84-0.91), and its optimal cutoff value was 2.05 mV in males (77.6% sensitivity and 74% specificity) and 1.935 mV in females (90.6% sensitivity and 91.4% specificity). Peguero voltage (beta = 0.154, P = 0.034) and SD (beta = 0.223 P = 0.004) were independently correlated with E/e', an index of left ventricular diastolic function. The Peguero voltage had high sensitivity and specificity for detecting the presence of HCM. It was positively correlated with E/e' in patients with HCM. For AHCM, the S-L voltage was more advantageous. Combining the S-L voltage with the Peguero voltage further improves the sensitivity for HCM and thus could be used to improve the screening of HCM in clinical practice. The SD and modified Cornell voltage also had good diagnostic performance, especially in females.

Left atrial strain and long-term risk of atrial fibrillation in hypertrophic cardiomyopathy

Abstract Background The prevalence of atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) patients is higher than in the general population, and it is associated with an increased risk of adverse outcomes, such as stroke, heart failure, and mortality. The left atrium (LA) plays an important role in maintaining normal cardiac function, and alterations in its structure and function can contribute to the development of AF. LA strain, a surrogate of LA remodeling, has been suggested a predictor of future AF. Purpose The aim of this study was to explore risk factors of new onset AF highlighting LA strain in patients with HCM. Methods Among a prospective cohort of 865 HCM patients collected at two large tertiary centers, 696 with adequate echocardiographic images to measure LA strain without a history of AF were included in the analysis. LA strain was measured on apical four-chamber view at initial evaluation using vendor-independent speckle-tracking software. The primary endpoint was new onset AF during 10 years after initial evaluation. Results The median age was 55.0 years and 74.3% were male. A median value of LA reservoir strain (LARS) was 26.2 % [interquartile range 20.4, 33.3]. Among the 696 patients, 66 had new onset AF 10 years, with a 10-year incidence of 15.8%. The unadjusted risk factors for new onset AF were previous stroke, non-apical HCM, family history of HCM, non-sustained ventricular tachycardia, obstructive HCM, extensive late gadolinium enhancement, larger LA diameter, larger LA volume, and lower LARS. LARS remained an independent predictor of new onset AF in multivariable analysis. The best cut-off value of LARS was 17.9% (hazard ratio 4.00, 95% confidence interval 2.44–6.55, p&amp;lt;0.001). Compared with LARS ≥17.9%, LARS &amp;lt;17.9% was significantly associated with a higher incidence of new onset AF, irrespective of presence of clinical risk factors (Figure 1) and LA enlargement (Figure 2). Conclusions In patients with HCM, low LA strain is an independent predictor of new onset AF.

Temporal Changes in Cardiac Morphology and Its Relationship with Clinical Characteristics and Outcomes in Patients with Hypertrophic Cardiomyopathy

In this study, we aimed to assess a large cohort of nonapical hypertrophic cardiomyopathy (HC) patients who have undergone 2 serial cardiac magnetic resonance studies to examine morphological dynamics and their correlation to patient characteristics and clinical outcomes. A total of 214 patients with nonapical HC were enrolled in this study, with 2 sequential cardiac magnetic resonance studies separated by a mean interval of 4.8±2.1years. Progression of indexed left ventricular mass (LVMI) was correlated with lower LVMI at baseline (p<0.00001) and older age >50 years. In terms of maximal wall thickness (MWT), progression was associated with lower baseline MWT and with the presence of LV outflow tract obstruction. No association was demonstrated between the degree of progression of LVMI or MWT and baseline LV volumes, the severity of mitral regurgitation, gender, or the presence of pathogenic HC variants. Progression of left atrial size was significantly associated with the development of atrial fibrillation (p=0.014; odds ratio 1.18, confidence interval 1.03 to 1.35) and admission for heart failure (p=0.018; odds ratio 1.18, confidence interval 1.03 to 1.36). No correlation was demonstrated between changes in LV mass or MWT and clinical outcomes of admission for heart failure, progression to New York Heart Association 2/3, progression to end-stage HC, or implantable cardioverter-defibrillator implantation. In conclusion, our study provides novel insights into the natural history of HC from a morphological perspective. It shows that HC is a dynamic disease in which LV morphology and hypertrophy extent change over time, with the presence of risk factors associated with disease progression.

A research on the relationship of genotypes and phenotypes in hypertrophic cardiomyopathy

Objective To explore the relationship between genotypes and phenotypes in hypertrophic cardiomyopathy(HCM) patients using whole exome sequencing(WES) and three-dimensional speckle-tracking echocardiography(3D-STE). Methods Twenty patients with apical HCM(ApHCM) and 25 patients with non-apical HCM(non-ApHCM) from June 2018 to January 2019 in Zhongshan Hospital of Fudan University were enrolled. All subjects underwent venous blood sampling and WES. Regular two-dimensional echocardiography was performed to acquire the following parameters: interventricular septum thickness, left ventricular posterior wall thickness, left ventricular end diastolic diameter, left ventricular end systolic diameter, the maximum thickness of left ventricular walls and left ventricular ejection fraction(LVEF). Full volume images were collected and then off-time analyzed with 3D-STE to acquire global longitudinal strain(GLS), global circumferential strain(GCS), twist and torsion. The relationships between above parameters, genotypes and phenotypes of left ventricle were analyzed. Results Mutations were found in 73% of HCM patients.The two most common genes MYBPC3 and MYH7 accounted for 18% and 15% of mutations respectively. KCNEc.79C>T(p.Arg27Cys) and PRKAG2c.905G>A (p.Arg302Gln) were detected in both ApHCM group and non-ApHCM group. In ApHCM group, 60% of patients carried genetic mutations, which was significantly lower than non-ApHCM group(84%)(P=0.041). Compared with non-ApHCM group, GLS in ApHCM group was significantly higher (P=0.008). There was no statistical difference of GLS between patients with mutations and without mutations(P=0.068). GLS demonstrated a moderate correlation with morphologic types of HCM(ApHCM and non-ApHCM)(r=0.364, P=0.012). However, there was no correlation between GLS and the condition of mutations(r=0.269, P=0.062). Conclusions The relationship between genetics and phenotypic expression of HCM appears to be complex and heterogeneous. There are marked differences in gene mutations and systolic functions between ApHCM and non-ApHCM. The value of GLS correlates with the shape of left ventricle but not with genotypes. Key words: Echocardiography, three-dimensional; Speckle tracking imaging; Hypertrophic cardiomyopathy; Mutations; Strain

Calculated Risk for Sudden Cardiac Death in Patients with Apical Versus Nonobstructive Nonapical Hypertrophic Cardiomyopathy

There are limited and conflicting data regarding the prognosis of patients with apical hypertrophic cardiomyopathy (HC) and their risk for sudden cardiac death (SCD). We used data from a single tertiary center for comparing the clinical course and the calculated risk for SCD in patients with nonobstructive apical HC (apical HC) versus patients with nonobstructive, nonapical HC (NONA HC). The 5-year SCD risk was calculated based on the HC risk-SCD tool. A total of 109 patients were included in the cohort of whom 44 (40%) patients were diagnosed with apical HC. The majority of patients were males with a median age at diagnosis of 40 years (interquartile range 26, 59 years). Patients with apical HC had a significant lower calculated 5-year risk for SCD compared with patients with NONA HC (2.65 ± 2.2% vs 4.00 ± 3.5%, respectively, p = 0.017), primarily due to a lower incidence of familial SCD (20% vs 43% respectively, p = 0.014). Only 9% of patients with apical HC had a calculated risk of >6% (implantable cardioverter-defibrillator recommended), as compared with 23% of patients with NONA HC. During a median follow-up of 1,018 days (interquartile range 546, 1449 days), apical HC patients tended to develop less malignant ventricular arrhythmia episodes compared with NONA HC patients (0% vs 7.7%, respectively, p = 0.060). In conclusion, apical HC patients have a lower calculated risk of SCD compared with NONA HC patients, mainly due to a lower incidence of family history of SCD. Thus, apical HC should be considered a form of HC less prone to SCD.

Incidence, Clinical Characteristics, and Long-term Outcome of the Dilated Phase of Hypertrophic Cardiomyopathy.

Some patients with hypertrophic cardiomyopathy (HCM) develop systolic dysfunction, called the dilated phase of HCM (d-HCM), which is associated with increased morbidity and mortality. We conducted a retrospective study using an HCM database to clarify the incidence, clinical characteristics, and long-term outcomes of d-HCM. We analyzed an HCM cohort consisting of 434 patients (273 with apical HCM and 161 with non-apical HCM; 18 had obstructive HCM, 16 had dilated HCM, and 127 had other HCM) diagnosed by echocardiography in our hospital between 1991 and 2010. The follow-up period was 8.4 ± 6.7 years. The mean age at final follow-up was 67 ± 14 years, and 304 patients (70%) were men. The mean age of the 16 d-HCM patients at the initial visit was 45 ± 17 years, the age at final follow-up was 59 ± 18 years, and 13 were men. Thirteen d-HCM patients developed atrial fibrillation and six patients developed ischemic stroke. Twelve d-HCM patients were implanted with cardiac devices: one pacemaker, nine implantable cardioverter-defibrillators, and two cardiac resynchronization therapy with defibrillator. Five patients died of progressive heart failure at the age of 61 ± 23 years. The age at the initial visit and final follow-up were lower and the NYHA class, brain natriuretic peptide levels, and left ventricular function at initial evaluation were worse in the d-HCM group. Univariate analysis demonstrated that a lower age at the initial visit was associated with d-HCM (hazard ratio 0.955/1 year increase; 95% CI 0.920-0.991, P = 0.015). In our HCM cohort, the incidence of d-HCM was 4%. A high prevalence of atrial fibrillation and cerebral infarction and poor prognosis were noted in this group, despite patients undergoing medication and device implantation.

6 Prevalence and CMR characteristics of apical HCM: Abstract 6 Table 1

Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death in young adults. The 3 main phenotypes are asymmetric (most common), concentric and apical. Literature suggests apical HCM is rare and more benign, but data is scarce. We sought to describe prevalence and characteristics of apical HCM in a large CMR service. Methods We reviewed 3,100 scans (Jan 2014–Mar 2015). Protocol included cines, early and late gadolinium enhancement imaging. 114 consecutive HCM patients were identified. Asymmetric HCM defined as septal/ free wall thickness ratio > 1.3; apical HCM as apical wall thickness > 15mm or apical/basal wall thicknesses ≥ 1.3–1.5. Concentric HCM defined as symmetrical hypertrophy of ventricular wall without regional preferences. Non-apical HCM (asymmetric and concentric phenotypes) were compared with apical HCM. Fisher’s exact t-test and unpaired t-test were performed for statistical significance (P-value Results 10 patients were excluded, leaving 104 patients, median age 60years; 70% male. 70% had non-apical HCM (5 patients concentric HCM, the rest asymmetric HCM) and 30% apical HCM. Mean maximum LV wall thickness, indexed LV mass, stroke volume, prevalence of LVOTO and SAM were greater in non-apical group. Presence of LGE was high in both groups (>85%) and wasn’t statistically different. Univariate predictors of apical HCM included maximum LV wall thickness, indexed stroke volume, LVOT obstruction (Table 1). In the multivariate model, maximum wall thickness remained the only significant predictor. Conclusions Our study suggests that prevalence of apical HCM is almost 1/3rd of all observed cases. It also demonstrates that prevalence of LGE was high in apical HCM, suggesting that better prognosis of apical HCM based on the absence of myocardial fibrosis, should be reconsidered. Further large trials are needed to better understand the pathophysiology.

5 Structural predictors of atrial fibrillation in hypertrophic cardiomyopathy using cardiac magnetic resonance imaging: Abstract 5 Table 1

Background Atrial fibrillation (AF) is the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM) and is associated with major adverse cardiovascular events. Cardiac magnetic resonance (CMR) with its superior tissue characterisation property is currently the imaging modality of choice for HCM. Aims To identify the structural predictors of AF in HCM using CMR. Methods 114 consecutive HCM patients were identified after reviewing approximately 3,100 CMR scans from our registry (Jan 2014 to Mar 2015). Comprehensive CMR protocol was used including cines, early and late gadolinium enhancement imaging. The diagnosis of HCM was based on left ventricular (LV) maximum wall thickness ≥15 mm (or 13–14 mm in the presence of familial history and/or ECG changes), in the absence of other cardiac/systemic disorders producing a similar degree of hypertrophy. Clinical notes were evaluated to identify a documented episode of AF. Univariate and multivariate logistic regression analyses were performed to determine the CMR imaging predictors of AF in HCM. Results The final study sample consisted of 104 patients with HCM with median age 60years (IQR = 54–70) and 70% male, (10 patients excluded due to uncertain/overlapping diagnosis). 70% had non-apical HCM; the remainder 30% apical HCM. 16% (n = 17) had a documented episode of atrial fibrillation. The univariate predictors of AF included left atrial volume and the ratio of left atrial volume to LV end systolic volume whereas in the multivariate model the ratio of left atrial volume to LV end systolic volume remained the only significant predictor (p = 0.034, OR = 2.236, CI = 1.06–4.70) (Table 1). Conclusion Our study suggests that the ratio of left atrial volume to LV end systolic volume is the best predictor of AF in HCM. The simple CMR derived ratio may have potential role for AF risk stratification in HCM.

Myocardial fibrosis progression on cardiac magnetic resonance in hypertrophic cardiomyopathy

ObjectiveWe hypothesised that, in hypertrophic cardiomyopathy (HCM), late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) is progressive and can be predicted by baseline CMR findings and HCM phenotype.MethodsIn this...

Extent of late gadolinium enhancement at right ventricular insertion points in patients with hypertrophic cardiomyopathy: relation with diastolic dysfunction.

Our aim was to examine the association between the extent of late gadolinium enhancement (LGE) at right ventricular insertion points (RVIP) and left ventricular (LV) functional parameters in patients with hypertrophic cardiomyopathy (HCM). Sixty-one HCM patients underwent echocardiography and cardiovascular magnetic resonance (CMR) within one week. Mitral annular velocities (E/E') were obtained from echocardiography; LV ejection fraction (EF), LV mass index, LV wall maximal thickness, and left atrial volume index (LAVI) were obtained from MR. LGE extent was quantified (proportion of total LV myocardial mass) according to location: % RVIP-LGE and % non-RVIP-LGE. Although LGE was commonly present in both apical (74 %) and non-apical HCMs (88 %) (p = 0.163), RVIP-LGE was more frequent (86 % vs. 47 %, p = 0.002) in non-apical HCMs in which E/E' was significantly higher (19.23 ± 8.40 vs. 13.13 ± 5.06, p = 0.009). In addition, RVIP-LGE extent was associated with LV diastolic dysfunction (r = 0.45, p < 0.001 for E/E'; r = 0.53, p < 0.001 for LAVI) and lower LVEF (r = -0.42, p = 0.001). There was no correlation between non-RVIP-LGE extent and other parameters. Multiple linear regression analysis revealed RVIP-LGE extent as an independent predictor of E/E' (β = 0.45, p < 0.001) and LAVI in HCM patients (β = 0.53, p < 0.001). The extent of LGE at RVIPs in HCM patients is associated with increased estimated LV filling pressure and chronic diastolic burden. • Late gadolinium enhancement at RV insertion points is frequently seen in HCM. • RVIP-LGE extent is correlated with increased estimated LV filling pressure in HCM. • Non-RVIP-LGE extent did not show any association with LV diastolic dysfunction.

WHY DOES APICAL HYPERTROPHIC CARDIOMYOPATHY HAVE A FAVORABLE OUTCOME THAN NON-APICAL TYPES? CARDIAC MAGNETIC RESONANCE AND ECHOCARDIOGRAPHIC FINDINGS FROM 350 PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY

Background Apical HCM tends to have a favorable outcome compared to other types. The presence and extent of late gadolinium enhancement (LGE), reflecting myocardial fibrosis, is closely correlated with increased cardiac mortality and strongly associated with surrogates of arrhythmia and subsequent sudden cardiac death. This study sough to investigate the difference in cardiac magnetic resonance (CMR) and echocardiographic and clinical manifestations between apical hypertrophic cardiomyopathy (HCM) and non-apical HCM.

Why does apical hypertrophic cardiomyopathy have a favorable outcome than non-apical types?: Cardiac magnetic resonance and echocardiographic findings from 350 patients with hypertrophic cardiomyopathy

Background Apical HCM tends to have a favorable outcome compared to other types. The presence and extent of late gadolinium enhancement (LGE), reflecting myocardial fibrosis, is closely correlated with increased cardiac mortality and strongly associated with surrogates of arrhythmia and subsequent sudden cardiac death. This study sough to investigate the difference in cardiac magnetic resonance (CMR) and echocardiographic and clinical manifestations between apical hypertrophic cardiomyopathy (HCM) and non-apical HCM.

T-wave inversions related to left ventricular basal hypertrophy and myocardial fibrosis in non-apical hypertrophic cardiomyopathy: A cardiovascular magnetic resonance imaging study

ObjectivesTo investigate the relationship between T-wave inversions and left ventricular (LV) segmental hypertrophy and myocardial fibrosis assessed by cardiovascular magnetic resonance (CMR) in patients with non-apical hypertrophic cardiomyopathy (HCM). Methods196 consecutive patients with non-apical HCM underwent late gadolinium enhancement (LGE) CMR and 12-lead electrocardiogram. The distribution and magnitude of LV segmental hypertrophy and LGE were assessed according to the AHA 17-segment model and analyzed in relation to T-wave inversions. ResultsOf 196 HCM patients, 144 (73%) exhibited T-wave inversions. 144 (73%) patients had evidence of myocardial fibrosis as defined by LGE, and the prevalence of LGE was significantly higher in patients with T-wave inversions compared with those without T-wave inversions (78% vs. 59%, P=0.008). T-wave inversions were related to basal anterior and basal anteroseptal LGE (20% vs. 10%, P=0.04 and 68% vs. 46%, P=0.005, respectively). In addition, T-wave inversions were associated with greater basal anteroseptal and basal inferior wall thickness (19.5±4.7mm vs. 16.7±4.5mm, P<0.001 and 10.9±3.3mm vs. 9.6±3.0mm, P=0.01, respectively). By logistic regression analysis, basal anteroseptal wall thickness and LGE were independent determinants of T-wave inversions (P=0.005, P=0.01, respectively). ConclusionsT-wave inversions in HCM are associated with LGE and wall thickness of the left ventricular basal segments. Moreover, basal anteroseptal wall thickness and LGE are independent determinants of T-wave inversions.

Degree and distribution of left ventricular hypertrophy as a determining factor for elevated natriuretic peptide levels in patients with hypertrophic cardiomyopathy: insights from cardiac magnetic resonance imaging

Whether the left ventricular (LV) mass index (LVMI) and LV volumetric parameters are associated independently with natriuretic peptide levels is unclear in hypertrophic cardiomyopathy (HCM). Therefore, we investigated which parameters have an independent relationship with N-terminal pro-B type natriuretic peptide (NT-proBNP) levels in HCM patients using echocardiography and cardiac magnetic resonance imaging (CMR). A total of 103 patients with HCM (82 men, age 53 ± 12 years) were evaluated. Echocardiographic evaluations included left atrial volume index (LAVI) and early diastolic mitral inflow E velocity to early annular Ea velocity ratio (E/Ea). LVMI, maximal wall thickness and LV volumetric parameters were measured using CMR. The median value of NT-proBNP level was 387.0 pg/ml. The mean NT-proBNP level in patients with non-apical HCM (n = 69; 36 patients with asymmetric septal hypertrophy, 11 with diffuse, and 22 with mixed type) was significantly higher than in those with apical HCM (n = 34, P < 0.001). NT-proBNP level was negatively correlated with LV end-diastolic volume (LVEDV) (r = -0.263, P = 0.007) and positively with LVMI (r = 0.225, P = 0.022) and maximal wall thickness (r = 0.495, P < 0.001). Among the echocardiographic variables, LAVI (r = 0.492, P < 0.001) and E/Ea (r = 0.432, P < 0.001) were correlated with NT-proBNP. On multivariable analysis, non-apical HCM, increased maximal wall thickness and LAVI were independently related with NT-proBNP. Severity of LV hypertrophy and diastolic parameters might be important in the elevation of NT-proBNP level in HCM. Therefore, further evaluation of these parameters in HCM might be warranted.

Sarcomere Protein Gene Mutations in Patients With Apical Hypertrophic Cardiomyopathy

Apical hypertrophic cardiomyopathy (HCM) is a unique form of HCM with left ventricular hypertrophy confined to the cardiac apex. The purpose of our study was to report genetic findings in a large series of unrelated patients with apical HCM and compare them with a nonapical HCM cohort. Overall, 429 patients with HCM underwent genetic testing. The panel included 8 sarcomere protein genes and 3 other genes (GLA, PRKAG2, and LAMP2). Sixty-one patients were diagnosed with apical HCM. A positive genotype was found in 8 patients with apical HCM. The genotype-positive and genotype-negative patients had similar maximal wall thicknesses (17.5 ± 3.5 mm versus 17.6 ± 3.3 mm, P = 0.71) and similar frequency of HCM-related events (2/8; 25% versus 13/53; 25%; P = 0.98). Thirteen percent with apical HCM and 40% with nonapical HCM had a positive genotype (P<0.001) most often involving the MYBPC3 and MYH7 genes. In apical HCM, a positive genotype was found less frequently than in nonapical HCM, and it was most often involving MYBPC3 and MYH7 genes. Only 13% of patients with apical HCM were found to be genotype positive, indicating that genome-wide association studies and gene expression profiling are needed for better understanding of the genetic background of the disease. There was no significant genotype-phenotype correlation in our cohort with apical HCM.

Left Atrial Volume Index: A Predictor of Adverse Outcome in Patients With Hypertrophic Cardiomyopathy

Despite the relatively benign course for the majority of patients with hypertrophic cardiomyopathy (HCM), this disease may cause sudden cardiac death and progressive heart failure (HF). The aim of this study was to investigate useful parameters for predicting adverse outcomes of HCM, including echocardiographic parameters, cardiac magnetic resonance (CMR), and clinical markers. Eighty-one patients with nonapical HCM (51 men; mean age, 57 +/- 14 years) who underwent CMR and echocardiography were prospectively evaluated. Cardiovascular events were defined as hospitalization for worsening HF, stroke, or cardiovascular death. During the mean follow-up period of 41 +/- 17 months, there were 17 cardiovascular events (5 deaths, 7 hospitalizations for worsening HF, and 5 strokes). Univariate analysis showed that older age, atrial fibrillation, elevated E/E' ratio, increased left atrial (LA) volume index, presence of mitral regurgitation grade > 2, New York Heart Association class III or IV, and late gadolinium enhancement >or= 6% were associated with cardiovascular events. In multivariate Cox regression analysis, increased LA volume index was found to be an independent predictor of cardiovascular events (for each 5 mL/m(2) increase, hazard ratio, 1.28; 95% confidence interval, 1.10-1.48; P < .01). Increased LA volume index was also revealed to be an independent predictor for cardiovascular events other than death (for each 5 mL/m(2) increase, hazard ratio, 1.44; 95% confidence interval, 1.12-1.83; P < .01). LA volume index is independently associated with adverse outcomes in patients with HCM and provides additional prognostic information.