The Relationship between Symptom Burden and Myocardial Fibrosis in Patients with Hypertrophic Cardiomyopathy.

Myocardial fibrosis assessed by late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) is associated with cardiovascular outcomes in hypertrophic cardiomyopathy (HCM) patients, but little is known about the utility of non-invasive markers for detecting LGE. This study aims to explore the association between cardiac-specific biomarkers, CMR myocardial strain, left ventricular (LV) hypertrophy and LGE in HCM patients with preserved ejection fraction (EF) and investigate the predictive values of these indexes for LGE. We recruited 33 healthy volunteers and 86 HCM patients with preserved EF to undergo contrast-enhanced CMR examinations. In total, 48 of 86 HCM patients had the presence of LGE. The LGE-positive patients had significant higher serum high-sensitivity cardiac troponin I (hs-cTnI) and N-terminal pro b-type natriuretic peptide (Nt-proBNP) levels and lower global longitudinal (GLS) and circumferential (GCS) strains than the LGE-negative group. The LGE% was independently associated with the Nt-proBNP levels, GCS, LV end-diastolic maximum wall thickness (MWT) and beta-blocker treatment. In the receiver operating characteristic curve analysis, the combined parameters of Nt-proBNP ≥ 108.00 pg/mL and MWT ≥ 17.30 mm had good diagnostic performance for LGE, with a specificity of 81.25% and sensitivity of 70.00%. These data indicate that serum Nt-proBNP is a potential biomarker associated with LGE% and, combined with MWT, were useful for identifying myocardial fibrosis in HCM patients with preserved EF. Additionally, LV GCS may be a more sensitive indicator for reflecting the presence of myocardial fibrosis than GLS.

A 48-year-old man, with only a history of mild systemic hypertension, was initially evaluated after presenting with symptoms of exertional dyspnea occurring predominantly with inclines. At that time, an abnormal 12-lead ECG was obtained demonstrating left ventricular hypertrophy by conventional voltage criteria, prompting additional testing with a 2-dimensional echocardiogram that showed normal systolic function (ejection fraction=65%), with 14-mm ventricular septal thickness and 12 mm in the posterolateral wall, and mild systolic anterior motion (SAM) of the mitral valve (bend of anterior leaflet into outflow tract without septal contact). A stress nuclear stress test showed no myocardial ischemia at rest or at peak exercise with a normal blood pressure response and no arrhythmias or ST-T changes during exercise or in recovery. The patient was prescribed a β-blocker for treatment of systemic hypertension. During the next 2 years, the patient developed more limiting exertional symptoms with routine activities. β-Blocker dosage was increased, and a repeat echocardiogram demonstrated similar findings to the initial study, borderline left ventricular (LV) wall thickness despite well-controlled blood pressure. The abnormal ECG, and mild SAM at rest, raised consideration for a diagnosis of hypertrophic cardiomyopathy (HCM) and management for limiting heart failure symptoms. HCM is often suspected in a patient based on the presence of cardiovascular symptoms, detection of abnormal ECG, systolic ejection murmur on routine examination, or as part of pedigree screening.1,2 Abnormalities on ECG are present in >90% of patients with HCM, although no specific ECG pattern is pathognomonic.1 Clinical diagnosis of HCM can reliably be made in the majority of patients with 2-dimensional transthoracic echocardiography by imaging increased LV wall thickness (≥15 mm) with a nondilated cavity in the absence of any disease known to cause LV hypertrophy of that magnitude (ie, systemic hypertension or aortic stenosis).1–5 In …

An asymptomatic athletic 42-year-old man has an abnormal 12-lead ECG obtained during his initial employment examination at a new job (Figure 1). He had no family history of hypertrophic cardiomyopathy (HCM) or unexplained sudden deaths. Echocardiogram demonstrated a 13-mm ventricular septal thickness without systolic anterior motion of the mitral valve. The patient exercised on a standard Bruce protocol stress (exercise) echocardiogram for 12 minutes, without symptoms or arrhythmias, and with appropriate blood pressure augmentation. In the immediate recovery period, systolic anterior motion was absent and outflow tract velocities were normal. A 24-hour ambulatory (Holter) ECG demonstrated normal sinus rhythm without ventricular ectopy. This clinical evaluation left a number of unanswered questions for the patient regarding the diagnosis of HCM, prognosis, and whether a genetic heart disease was present in his family. Figure 1. Abnormal 12-lead ECG in a 42-year-old man demonstrating normal sinus rhythm with left anterior fascicular block, RSR′ in leads V1 and V2, and left ventricular hypertrophy. Since the early 1970s, cardiovascular imaging has played a critical role in describing the structure and function of the heart in HCM.1–5 Indeed, HCM is a disorder uniquely suited to noninvasive imaging, given HCM’s characteristic heterogeneous morphology and hemodynamics, including dynamic left ventricular (LV) outflow obstruction.2,3 For much of 40 years, echocardiography has been the dominant imaging technique, first with rudimentary M-mode and then ultimately 2-dimentional imaging and Doppler,2 now widely available and accessible. The past decade has witnessed the introduction of cardiac magnetic resonance (CMR) into clinical HCM practice.1,3–10 This contemporary technique provides images with high spatial and temporal resolution and sharp contrast between the myocardial border and blood pool, allowing precise measurements of LV wall thickness and complete tomographic reconstruction of the entire cardiac chamber (without …

Background Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death in young individuals and an important cause of heart failure at any given age. Lumican, is an indicator of fibrosis and has been studied in various cardiac conditions. In this study, we aimed to evaluate the relation between serum Lumican levels and presence and extent of myocardial fibrosis in HCM. Methods The patients diagnosed with HCM between June 2022 and March 2023 were enrolled consecutively in this prospective study. Age and gender-matched healthy individuals formed control group. Additionally, HCM patients divided into two groups according to extent of late gadolinium enhancement (LGE). Results A total of 114 patients (62.3% male, 54.5±9.4 mean age) were enrolled in this prospective study. 64 patients formed HCM (+) and 50 patients formed HCM (-) group. The HCM (+) group is divided into two groups as LGE (+) and LGE (-) according to LGE involvement. Serum Lumican [p=0.018, β: 1.561, OR (95% CI): 1.080-2.257], NT-proBNP [p=0.043, β: 1.209, OR (95% CI): 1.079-2.527] and maximum wall thickness (MWT) [p=0.033, β: 1.322, OR (95% CI): 1.023-1.707] were revealed as independent risk factors associated with LGE by multivariate logistic regression analysis (Figure 1). ROC curve analysis was performed to identify the optimal cut-off value and calculate area under the curve (AUC) for Lumican, troponin (Tn) and NT-proBNP in order to predict the presence and extent of LGE in patients with HCM. A cut off value of 9.06 for Lumican was associated with 67.8% sensitivity and 65.5% specificity in prediction of LGE. A cut-off value of 932.4 for NT-proBNP was associated with 60% sensitivity, 60% specificity in prediction of LGE. Conclusion Myocardial fibrosis is one of the important mechanisms in HCM pathophysiology. Although LGE on cardiac magnetic resonance imaging(CMR) allows comprehensive evaluation of myocardial fibrosis, the support of diagnosis with a biomarker would be beneficial in clinical practice.Our study revealed that serum Lumican level is an independent predictor of severe LGE in HCM patients. Lumican can be used in addition to CMR for evaluating extence of myocardial fibrosis in HCM patients and may help clinicians in guiding follow-up and treatment.

The feasibility and diagnostic value of intravoxel incoherent motion diffusion-weighted imaging in the assessment of myocardial fibrosis in hypertrophic cardiomyopathy patients

PROGRESSION OF LATE GADOLINIUM ENHANCEMENT IN HYPERTROPHIC CARDIOMYOPATHY

Background Strain techniques, such as feature tracking cardiac magnetic resonance (FT-CMR), have emerged as a promise for more accurate evaluation of cardiac function compared to ejection fraction. In hypertrophic cardiomyopathy (HCM) patients, impaired myocardial deformation measured by FT-CMR has been associated with severity of hypertrophy and presence of late gadolinium enhancement (LGE) but associations with clinical severity and prognosis are scarce. Purpose To analyse the association between left ventricular strain measured by FT-CMR, morphologic features and prognostic markers in patients with HCM. Methods Retrospective analysis of clinical, echocardiography, Holter and CMR data of HCM patients aged ≥16 years followed at two referral centres. Ventricular arrhythmias (VA) were defined as non-sustained or sustained ventricular tachycardia or sudden cardiac arrest. Sudden cardiac death (SCD) risk was evaluated using the score proposed by the European Society of Cardiology. LGE extension was evaluated using the American Heart Association 17-segment model. FT-CMR was used to evaluate global peak systolic longitudinal (GLS), radial (GRS) and circumferential (GCS) strains - GLS was averaged from three standard longitudinal views while GRS and GCS were averaged from the basal, mid and apical LV short-axis planes. Results A total of 109 HCM patients (59.2±16.2 years old; 60.6% males) were included; mean follow-up was 39±25 months. Mean LV mass was 170.6±70.3g, LVEF was 63.7±10.0% and the number of segments with LGE was 3.14±3.32. Mean GLS, GRS and GCS were −14.8±4.0%, 34.4±13.3% and −17.5±4.8%, respectively. Impaired strain was associated with higher LV mass (GLS: r=0.46, GRS: r=−0.46, GCS: r=0.47, p<0.001 for all), reduced LVEF (GLS: r=−0,33, GRS: r=0,44, GCS: r=−0.41, p<0.003 for all) and LGE extension (GLS: r=0.26, GRS: r=−0.38, GCS: r=0.38, p<0.01 for all). SCD risk score was 3.12%±2.98 (8 patients scored as high risk) and VA were documented in 26 patients (26%). Patients with VA had worse strain values than those without (GLS −13.2±4.12 vs −15.5±3.71, p=0.011; GCS −15,8±5.22 vs −18.3±4.24, p=0.017). Patients with high estimated risk of SCD also had worse strain values than those at low/intermediate risk (GLS −12.2±3.57 vs −15.1±3.83, p=0.048; GCS −14.5±4.26 vs −17.9±4.54, p=0.047). A correlation between SCD risk and GLS and GCS was observed (r=0.32, p=0.004; r=0.23, p=0.03, respectively). Conclusions In our population, worse strain measurements were associated with a more severe HCM phenotype, presence of VA and a higher estimated risk of SCD. Strain assessed by FT-CMR may improve risk stratification in HCM patients.

A 20-year-old asymptomatic man was diagnosed with hypertrophic cardiomyopathy (HCM) after routine physical examination during which a systolic heart murmur was detected.Echocardiography showed massive left ventricular (LV) hypertrophy with ventricular septal thickness of 36 mm extending into the anterolateral wall (30 mm); outflow obstruction was absent.Ambulatory (Holter) ECG showed 3 isolated premature ventricular contractions, and blood pressure response to exercise was normal.Echocardiographic examinations in parents and siblings were negative for HCM.Although 2 centers advised against an implantable cardioverter-defibrillator (ICD) based on the presence of only 1 risk factor for sudden death (ie, extreme hypertrophy), a prophylactic device was recommended by a third cardiac consultant.After an uneventful 16-month period during which the ICD neither detected nor treated arrhythmias, an unprovoked episode of ventricular fibrillation triggered a defibrillation shock that immediately restored sinus rhythm (Figure 1).

The aim of this study was to investigate the relationship between QT (QTc) interval, Tp-e interval, Tp-e/QTc ratio, 5-year sudden cardiac death (SCD) risk score, and late gadolinium enhancement (LGE) detected by CMR in hypertrophic cardiomyopathy (HCM) patients. A total of 74 consecutive patients who underwent CMR with HCM diagnosis were included in the study. These patients were divided into two groups according to the presence of LGE on CMR. All patients underwent detailed echocardiography and QTc interval, Tp-e interval, and Tp-e/QTc ratios and 5-year SCD risk scores were calculated. These parameters were compared for two groups. CMR revealed LGE in 32 (43.2%) of 74 HCM patients. In the group with LGE, significantly higher QTc interval (p=0.002), Tp-e interval (p<0.001), Tp-e/QTc ratio (p=0.004), and 5-year SCD risk score were detected. In addition, QTc interval, Tp-e interval, Tp-e/QTc ratio, maximum wall thickness, left ventricular mass index, 5-year SCD risk score, and cardiac fibrosis index were found to be correlated with various degrees in correlation analysis. Also, Tp-e interval is found to be an independent predictor of LGE detected by CMR in HCM patients (p=0.017, OR [%95 CI] = 1.017 [1.001-1.034]). In addition, the Tp-e interval can detect the LGE with a sensitivity of 64.3% and a specificity of 84.2% at 99.4ms. (p<0.001, AUC [95% CI] = 0.790 [0.676-0.905]). The Tp-e interval can be used to optimize SCD risk stratification in HCM patients and determine which patients will benefit from implantable cardioverter-defibrillator (ICD) treatment.

The stratification of risk for sudden death in hypertrophic cardiomyopathy (HCM) continues to be a true challenge due to the great heterogeneity of this disease's presentation, as most individuals remain asymptomatic during their entire lives and others present sudden death as first symptom. Recent studies have suggested that myocardial fibrosis may represent an important substrate for the malignant ventricular arrhythmias, that are responsible for the cases of sudden death related to this disease.To assess the prevalence and quantification of myocardial fibrosis (MF) in hypertrophic cardiomyopathy (HCM) patients with implantablecardioverter - defibrillator (ICD) indicated due to their high risk or recovered from cardiac sudden death.Twenty-eight HCM patients with ICD were submitted to multidetector computed tomography to assess myocardial fibrosis by delayed enhancement technique.Myocardial fibrosis was present in 96% of these HCM patients with (20.38 +/- 15.55 g) comprising 15.96 +/- 10.20% of the total myocardial mass. MF was observed in a significantly higher prevalence as compared to other classical risk factors for sudden death.It is possible to conclude that there is a high prevalence of myocardial fibrosis in hypertrophic cardiomyopathy patients with high-risk or recovered from cardiac sudden death, like those with clinical indication to implantable cardioverter -defibrillator. The higher prevalence of myocardial fibrosis in comparison to classical risk factors of worse prognosis raise the hypothesis that the myocardial fibrosis may be an important substrate in the genesis of lifethreatening arrhythmias in these high risk HCM population.

Introduction: In hypertrophic cardiomyopathy (HCM), there are significant variations in left ventricular (LV) wall thickness and fibrosis, which necessitates a volumetric coverage. Slice-interleaved T1 (STONE) mapping sequence allows for the assessment of native T1 time with complete coverage of LV myocardium. Hypothesis: We hypothesized that STONE sequence is useful for the assessment of regional native T1 time abnormality in HCM patients. Methods: Twenty-four septal HCM patients (56±16 years) and 10 healthy adult control subjects (57±15 years) were studied. Native T1 mapping was performed using STONE sequence which enables acquisition of 5 slices in the short-axis plane within a 90 sec free-breathing scan. We measured LV native T1 time and maximum LV wall thickness in each 16 segments from 3 slices (basal-, mid- and apical-slice) and evaluated the relationship between LV native T1 time and wall thickness. Late gadolinium enhanced (LGE) MRI was acquired to assess presence of myocardial enhancement. Results: In HCM patients, LV native T1 time was significantly elevated compared to healthy controls, regardless of presence or absence of LGE (mean native T1 time; LGE (+) segments (n=27), 1139±55 msec; LGE (-) segments (n=351), 1118±55 msec; healthy control (n=160),1065±35 msec; p&lt;0.001 by one-way ANOVA, 6 segments were excluded from analysis due to artifacts). Among 351 segments without LGE, native LV T1 time was diffusely elevated over the 16 segments (Figure). Significant positive correlation was found between LV wall thickness and native LV T1 time (y=1013+8.7x, p&lt;0.001). Conclusions: In HCM, substantial number of segments without LGE showed elevated native T1 time, and native T1 time was correlated with LV wall thickness. Multi-slice T1 mapping by using STONE sequence could be advantageous to overcome limited cardiac coverage of conventional single-slice T1 mapping technique and to accurately detect the diffuse myocardial fibrosis in HCM patients.

BackgroundsPrevious studies have shown that diffusion-weighted cardiovascular magnetic resonance (DW-CMR) is highly sensitive to replacement fibrosis of chronic myocardial infarction. Despite this sensitivity to myocardial infarction, DW-CMR has not been established as a method to detect diffuse myocardial fibrosis. We propose the application of a recently developed DW-CMR technique to detect diffuse myocardial fibrosis in hypertrophic cardiomyopathy (HCM) patients and compare its performance with established CMR techniques.MethodsHCM patients (N = 23) were recruited and scanned with the following protocol: standard morphological localizers, DW-CMR, extracellular volume (ECV) CMR, and late gadolinium enhanced (LGE) imaging for reference. Apparent diffusion coefficient (ADC) and ECV maps were segmented into 6 American Heart Association (AHA) segments. Positive regions for myocardial fibrosis were defined as: ADC > 2.0 μm2/ms and ECV > 30 %. Fibrotic and non-fibrotic mean ADC and ECV values were compared as well as ADC-derived and ECV-derived fibrosis burden. In addition, fibrosis regional detection was compared between ADC and ECV calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) using ECV as the gold-standard reference.ResultsADC (2.4 ± 0.2 μm2/ms) of fibrotic regions (ADC > 2.0 μm2/ms) was significantly (p < 0.01) higher than ADC (1.5 ± 0.2 μm2/ms) of non-fibrotic regions. Similarly, ECV (35 ± 4 %) of fibrotic regions (ECV > 30 %) was significantly (p < 0.01) higher than ECV (26 ± 2 %) of non-fibrotic regions. In fibrotic regions defined by ECV, ADC (2.2 ± 0.3 μm2/ms) was again significantly (p < 0.05) higher than ADC (1.6 ± 0.3 μm2/ms) of non-fibrotic regions. In fibrotic regions defined by ADC criterion, ECV (34 ± 5 %) was significantly (p < 0.01) higher than ECV (28 ± 3 %) in non-fibrotic regions. ADC-derived and ECV-derived fibrosis burdens were in substantial agreement (intra-class correlation = 0.83). Regional detection between ADC and ECV of diffuse fibrosis yielded substantial agreement (κ = 0.66) with high sensitivity, specificity, PPV, NPV, and accuracy (0.80, 0.85, 0.81, 0.85, and 0.83, respectively).ConclusionDW-CMR is sensitive to diffuse myocardial fibrosis and is capable of characterizing the extent of fibrosis in HCM patients.

To investigate the feasibility of automatic machine learning (autoML) based on native T1 mapping to predict late gadolinium enhancement (LGE) status in hypertrophic cardiomyopathy (HCM). Ninety-one HCM patients and 44 healthy controls who underwent cardiovascular MRI were enrolled. The native T1 maps of HCM patients were classified as LGE ( +) or LGE (-) based on location-matched LGE images. An autoML pipeline was implemented using the tree-based pipeline optimization tool (TPOT) for 3 binary classifications: LGE ( +) and LGE (-), LGE (-) and control, and HCM and control. TPOT modeling was repeated 10 times to obtain the optimal model for each classification. The diagnostic performance of the best models by slice and by case was evaluated using sensitivity, specificity, accuracy, and microaveraged area under the curve (AUC). Ten prediction models were generated by TPOT for each of the 3 binary classifications. The diagnostic accuracy obtained with the best pipeline in detecting LGE status in the testing cohort of HCM patients was 0.80 by slice and 0.79 by case. In addition, the TPOT model also showed discriminability between LGE (-) patients and control (accuracy: 0.77 by slice; 0.78 by case) and for all HCM patients and controls (accuracy: 0.88 for both). Native T1 map analysis based on autoML correlates with LGE ( +) or (-) status. The TPOT machine learning algorithm could be a promising method for predicting myocardial fibrosis, as reflected by the presence of LGE in HCM patients without the need for late contrast-enhanced MRI sequences. • The tree-based pipeline optimization tool (TPOT) is a machine learning algorithm that could help predict late gadolinium enhancement (LGE) status in patients with hypertrophic cardiomyopathy. • The TPOT could serve as an adjuvant method to detect LGE by using information from native T1 maps, thus avoiding the need for contrast agent. • The TPOT also detects native T1 map alterations in LGE-negative patients with hypertrophic cardiomyopathy.

Sudden cardiac death (SCD) is the most dramatic and catastrophic complication of hypertrophic cardiomyopathy (HCM),1 with an annual rate of &gt;1%.1 The identification of those patients most likely to benefit from prophylacticimplantable cardioverter defibrillators remains challenging in children and adults. The positive predictive value for appropriate discharges is low (≈20%), and the complication rates in this younger, active population is substantial, including lead problems, infections, inappropriate discharges, and psychological issues

To evaluate the ability of late gadolinium enhancement (LGE) and mapping cardiac magnetic resonance (CMR) including native T1 and global extracellular volume (ECV) to identify hypertrophic cardiomyopathy (HCM) patients at risk for sudden cardiac death (SCD) and to predict syncope or non-sustained ventricular tachycardia (VT). A 1.5-T CMR was performed in 73 HCM patients and 16 controls. LGE size was quantified using the 3SD, 5SD and full width at half maximum (FWHM) method. T1 and ECV maps were generated by a 3(3)5 modified Look-Locker inversion recovery sequence. Receiver-operating curve analysis evaluated the best parameter to identify patients with increased SCD risk ≥4% and patients with syncope or non-sustained VT. Global ECV was the best predictor of SCD risk with an area under the curve (AUC) of 0.83. LGE size was significantly inferior to global ECV with an AUC of 0.68, 0.70 and 0.70 (all P < 0.05) for 3SD-, 5SD- and FWHM-LGE, respectively. Combined use of the SCD risk score and global ECV significantly improved the diagnostic accuracy to identify HCM patients with syncope or non-sustained VT. Combined use of the SCD risk score and global ECV has the potential to improve HCM patient selection, benefiting most implantable cardioverter defibrillators. • Global ECV identified the best HCM patients with increased SCD risk. • Global ECV performed equally well compared to a SCD risk score. • Combined use of the SCD risk score and global ECV improved test accuracy. • Combined use potentially improves selection of HCM patients for ICD implantation.