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Background: The prognostic significance of focal and diffuse myocardial fibrosis in patients with cardiovascular risk factors is unclear. Methods: REMODEL (Response of the Myocardium to Hypertrophic Conditions in the Adult Population) is an observational cohort of asymptomatic patients with essential hypertension. All participants underwent cardiovascular magnetic resonance to assess for myocardial fibrosis: nonischemic late gadolinium enhancement (LGE), native myocardial T1, postcontrast myocardial T1, extracellular volume fraction including/excluding LGE regions, interstitial volume (extracellular volume×myocardial volume), and interstitial/myocyte ratio. Primary outcome was a composite of first occurrence acute coronary syndrome, heart failure hospitalization, strokes, and cardiovascular mortality. Patients were recruited from February 2016 and followed until June 2021. Results: Of the 786 patients with hypertension (58±11 years; 39% women; systolic blood pressure, 130±14 mm Hg), 145 (18%) had nonischemic LGE. Patients with nonischemic LGE were more likely to be men, have diabetes, be current smokers, and have higher blood pressure ( P 2 ; P P P P =0.002) demonstrated independent association with primary outcome. Conclusions: In patients with hypertension, myocardial fibrosis on cardiovascular magnetic resonance is associated with adverse cardiac remodeling and outcomes.

Background: Hypertrophic cardiomyopathy (HCM) is defined as left ventricular end-diastolic maximal wall thickness (WTMax) ≥15.0 mm, without accounting for ethnicity, sex, and body size. It is well-established that Asians have smaller hearts than do Caucasians. Objectives: This study aims to examine the implications of this single absolute WTMax threshold on the diagnosis of HCM in Asians. Methods: The study consisted of 360 healthy volunteers (male: n = 174; age: 50 ± 12 years) and 114 genetically characterized patients with HCM (male: n = 83; age: 52 ± 13 years; genotype-positive, n = 39). All participants underwent cardiovascular magnetic resonance. WTMax was measured semiautomatically at end-diastole according to the standard 16 myocardial segments. Results: Healthy male volunteers had increased WTMax compared with that of female volunteers (8.4 ± 1.2 mm vs 6.6 ± 1.1 mm, respectively; P < 0.001). Conversely, WTMax was similar between male and female patients with HCM (15.2 ± 3.4 mm vs 14.7 ± 3.0 mm, respectively; P = 0.484) and between those with and without a pathogenic gene variant (P = 0.828). Using the recommended diagnostic threshold of 15.0 mm, 56 patients with HCM had WTMax 15.0 mm (specificity of 100% and sensitivity of 51%). Lowering WTMax thresholds to 10.0 mm in female patients and 12.0 mm in male patients did not affect specificity (100%) but significantly improved sensitivity (84%). Despite lower left ventricular mass, female patients with HCM demonstrated more features of adverse cardiac remodeling than did male patients: increased myocardial fibrosis, higher asymmetric ratio, and disproportionately worse myocardial strain. Conclusions: The study highlights cautious application of guideline-recommended WTMax to diagnose HCM in Asians. Lowering WTMax to account for ethnicity and sex improves diagnostic sensitivity without compromising specificity.

Supplemental Digital Content is available in the text., Background: To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry. Methods: We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3634), compared findings with additional populations and White HCM cohorts (n=6179), and performed in vitro functional studies. Results: Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (pathogenic/likely pathogenic: 18%, P

Objectives The imaging features of dilated cardiomyopathy (DCM) overlap with physiological exercise-induced cardiac remodeling in active and otherwise healthy individuals. Distinguishing the two conditions is challenging. This study examined the diagnostic and prognostic roles of exercise stress imaging in asymptomatic patients with suspected DCM. Methods Exercise stress cardiovascular magnetic resonance (CMR) was performed in 60 asymptomatic patients with suspected DCM (dilated left ventricle and/or impaired systolic function on CMR), who also underwent DNA sequencing for DCM-causing genetic variants. Confirmed DCM was defined as genotype- and phenotype-positive (G+P+). Another 100 healthy subjects were recruited to establish normal exercise capacities (peak exercise cardiac index; PeakCI). The primary outcome was a composite of all-cause mortality, cardiac decompensation and ventricular arrhythmic events. Results No patients with confirmed G+P+ DCM had PeakCI exceeding the 35th percentile specific for age and sex. Applying this threshold in G-P+ patients, those with PeakCI below 35th percentile had characteristics similar to confirmed DCM while patients with higher PeakCI were younger, more active and higher longitudinal strain. Adverse cardiovascular events occurred only in patients with low exercise capacity (P = 0.004). Conclusions In individuals with suspected DCM, exercise stress CMR demonstrates diagnostic and prognostic potential in distinguishing between pathological DCM and physiological exercise-induced cardiac remodeling.

The role of left atrial (LA) strain as an imaging biomarker in aortic stenosis is not well established. The aim of this study was to investigate the prognostic performance of phasic LA strain in relation to clinical and echocardiographic variables and N-terminal pro-B-type natriuretic peptide in asymptomatic and minimally symptomatic patients with moderate to severe aortic stenosis and left ventricular ejection fraction50%.LA reservoir strain (LASr), LA conduit strain (LAScd), and LA contractile strain (LASct) were measured using speckle-tracking echocardiography. The primary outcome was a composite of all-cause mortality, heart failure hospitalization, progression to New York Heart Association functional class III or IV, acute coronary syndrome, or syncope. Secondary outcomes 1 and 2 comprised the same end points but excluded acute coronary syndrome and additionally syncope, respectively. The prognostic performance of phasic LA strain cutoffs was evaluated in competing risk analyses, aortic valve replacement being the competing risk.Among 173 patients (mean age, 69 ± 11 years; mean peak transaortic velocity, 4.0 ± 0.8 m/sec), median LASr, LAScd, and LASct were 27% (interquartile range [IQR], 22%-32%), 12% (IQR, 8%-15%), and 16% (IQR, 13%-18%), respectively. Over a median of 2.7 years (IQR, 1.4-4.6 years), the primary outcome and secondary outcomes 1 and 2 occurred in 66 (38%), 62 (36%), and 59 (34%) patients, respectively. LASr20%, LAScd6%, and LASct12% were identified as optimal cutoffs of the primary outcome. In competing risk analyses, progressing from echocardiographic to echocardiographic-clinical and combined models incorporating N-terminal pro-B-type natriuretic peptide, LA strain parameters outperformed other key echocardiographic variables and significantly predicted clinical outcomes. LASr20% was associated with the primary outcome and secondary outcome 1, LAScd6% with all clinical outcomes, and LASct12% with secondary outcome 2. LAScd6% had the highest specificity (95%) and positive predictive value (82%) for the primary outcome, and competing risk models incorporating LAScd6% had the best discriminative value.In well-compensated patients with moderate to severe aortic stenosis and preserved left ventricular ejection fractions, LA strain was superior to other echocardiographic indices and incremental to N-terminal pro-B-type natriuretic peptide for risk stratification. LAScd6%, LASr20%, and LASct12% identified patients at higher risk for adverse outcomes.

Clinical guidelines recommend that the exercise protocol of a stress echocardiogram is selected to induce volitional exhaustion after a target duration of at least 8 minutes. While the Bruce protocol is very commonly used for clinical stress tests, it is known to be "steep", and many patients therefore fail to reach 8 minutes. We studied predictors of failure and developed a method for identifying patients not suitable for Bruce protocol which was accurate and yet simple enough to be used as a point-of-care decision support tool.We studied data out-patients undergoing Bruce protocol stress echocardiograms (n = 11 086) and analyzed predictors of inappropriate early termination (defined as test duration 8 min as per current practice guidelines) using logistic regression. A prediction model was constructed as follows: .5 points were given for each of hypertension, diabetes, smoking, and E/e' 7.9 in the resting echocardiogram; .1 point was added for each 1-unit increment in body mass index; 1 point was added for patient age by decade; 2.0 points were subtracted for male sex (p for all 0.001). In tests on held-out validation data, the model was well calibrated (in plots of predicted vs actual risk) and discriminated failure versus non-failure well (C-statistic .86 for a score of 6.0 points; p 0.001).These data may help to standardize protocol selection in stress echocardiography, by identifying patients pre-hoc where Bruce protocol will be inappropriately steep.

Aims Hypertrophic cardiomyopathy (HCM) is characterized by cardiomyocyte hypertrophy and disarray, and myocardial stiffness due to interstitial fibrosis, which result in impaired left ventricular filling and diastolic dysfunction. The latter manifests as exercise intolerance, angina, and dyspnoea. There is currently no specific treatment for improving diastolic function in HCM. Here, we investigated whether myeloperoxidase (MPO) is expressed in cardiomyocytes and provides a novel therapeutic target for alleviating diastolic dysfunction in HCM. Methods and results Human cardiomyocytes derived from control-induced pluripotent stem cells (iPSC-CMs) were shown to express MPO, with MPO levels being increased in iPSC-CMs generated from two HCM patients harbouring sarcomeric mutations in the MYBPC3 and MYH7 genes. The presence of cardiomyocyte MPO was associated with higher chlorination and peroxidation activity, increased levels of 3-chlorotyrosine-modified cardiac myosin binding protein-C (MYBPC3), attenuated phosphorylation of MYBPC3 at Ser-282, perturbed calcium signalling, and impaired cardiomyocyte relaxation. Interestingly, treatment with the MPO inhibitor, AZD5904, reduced 3-chlorotyrosine-modified MYBPC3 levels, restored MYBPC3 phosphorylation, and alleviated the calcium signalling and relaxation defects. Finally, we found that MPO protein was expressed in healthy adult murine and human cardiomyocytes, and MPO levels were increased in diseased hearts with left ventricular hypertrophy. Conclusion This study demonstrates that MPO inhibition alleviates the relaxation defect in hypertrophic iPSC-CMs through MYBPC3 phosphorylation. These findings highlight cardiomyocyte MPO as a novel therapeutic target for improving myocardial relaxation associated with HCM, a treatment strategy which can be readily investigated in the clinical setting, given that MPO inhibitors are already available for clinical testing., Graphical Abstract

Background The MitraClip system has been used extensively in high-risk patients with severe degenerative mitral regurgitation (MR). Recent reports have demonstrated the feasibility of using the MitraClip device to treat systolic anterior motion (SAM) of the mitral valve in obstructive hypertrophic cardiomyopathy (HOCM). Case summary We report the case of a 76-year-old lady who had both symptomatic severe degenerative MR and HOCM that were refractory to medical therapy. Both pathologies were treated successfully using the MitraClip system. Discussion In patients who are deemed to be at high risk for open surgery, our case demonstrated the feasibility of a percutaneous avenue, the MitraClip system, to treat not just degenerative MR, but also SAM from HOCM in a single procedure.

Introduction Hypertrophic cardiomyopathy (HCM) is characterised by great phenotypic diversity and broad spectrum of clinical courses. The genetic, environmental and phenotypic determinants of outcome remain poorly understood. We integrated machine-learning analysis of cardiovascular magnetic resonance (CMR) with computational modelling to define the effects of genetic variation on the heart in both HCM patients and heathy volunteers. Methods Healthy volunteers were recruited at Imperial College London (n=1367) and National Health Centre Singapore (n=754). Patients with HCM were enrolled at the Royal Brompton Hospital (n=622) and National Heart Centre Singapore (n=211). Participants underwent conventional CMR at 1.5 T. Using cardiac atlas and machine learning techniques, CMRs were segmented and co-registered providing statistical models of phenotypic variation. Subjects were sequenced with comprehensive gene panels and using stringent criteria identified as genotype positive (G+), negative (G-) or as carriers of variants of unknown significance (VUS). Results In healthy volunteers, sarcomeric G+variants were associated with increased septal and apical LV wall thickness. In HCM, sarcomeric thin filament G+displayed the mildest global hypertrophy. Sarcomeric thick filament G+variants were associated with asymmetric septal hypertrophy, when compared to G-, VUS and other G+. Conclusion We show that in a healthy population, rare variants in sarcomeric genes are penetrant and associated with increased wall thickness. This has potential clinical implications to the ~0.5% of the population that are carriers. In HCM, distinct patterns of hypertrophy were associated with specific genotypes. We demonstrate that machine-learning analysis of CMRs offers unparalleled insights into the earliest manifestations of cardiomyopathy and mutation-specific pathophysiology.

IMPORTANCE: The genetic variant MYBPC3(Δ25bp) occurs in 4% of South Asian descendants, with an estimated 100 million carriers worldwide. MYBPC3 (Δ25bp) has been linked to cardiomyopathy and heart failure. However, the high prevalence of MYBPC3(Δ25bp) suggests that other stressors act in concert with MYBPC3(Δ25bp). OBJECTIVE: To determine whether there are additional genetic factors that contribute to the cardiomyopathic expression of MYBPC3(Δ25bp). DESIGN, SETTING, ANDPARTICIPANTS: South Asian individuals living in the United States were screened for MYBPC3(Δ25bp), and a subgroup was clinically evaluated using electrocardiograms and echocardiograms at Loyola University, Chicago, Illinois, between January 2015 and July 2016. MAIN OUTCOMES AND MEASURES: Next-generation sequencing of 174 cardiovascular disease genes was applied to identify additional modifying gene mutations and correlate genotype-phenotype parameters. Cardiomyocytes derived from human-induced pluripotent stem cells were established and examined to assess the role of MYBPC3(Δ25bp). RESULTS: In this genotype-phenotype study, individuals of South Asian descent living in the United States from both sexes (36.23% female) with a mean population age of 48.92 years (range, 18-84 years) were recruited. Genetic screening of 2401 US South Asian individuals found an MYBPC3(Δ25bp)carrier frequency of 6%. A higher frequency of missense TTN variation was found in MYBPC3(Δ25bp) carriers compared with noncarriers, identifying distinct genetic backgrounds within the MYBPC3(Δ25bp) carrier group. Strikingly, 9.6% of MYBPC3(Δ25bp) carriers also had a novel MYBPC3 variant, D389V. Family studies documented D389V was in tandem on the same allele as MYBPC3(Δ25bp), and D389V was only seen in the presence of MYBPC3(Δ25bp). In contrast to MYBPC3(Δ25bp), MYBPC3(Δ25bp/D389V) was associated with hyperdynamic left ventricular performance (mean [SEM] left ventricular ejection fraction, 66.7 [0.7%]; left ventricular fractional shortening, 36.6 [0.6%]; P

Background: Identification of people with hypertrophic cardiomyopathy (HCM) who are at risk of sudden cardiac death (SCD) and require a prophylactic implantable cardioverter defibrillator is challenging. In 2014, the European Society of Cardiology proposed a new risk stratification method based on a risk prediction model (HCM Risk-SCD) that estimates the 5-year risk of SCD. The aim was to externally validate the 2014 European Society of Cardiology recommendations in a geographically diverse cohort of patients recruited from the United States, Europe, the Middle East, and Asia. Methods: This was an observational, retrospective, longitudinal cohort study. Results: The cohort consisted of 3703 patients. Seventy three (2%) patients reached the SCD end point within 5 years of follow-up (5-year incidence, 2.4% [95% confidence interval {CI}, 1.9–3.0]). The validation study revealed a calibration slope of 1.02 (95% CI, 0.93–1.12), C-index of 0.70 (95% CI, 0.68–0.72), and D-statistic of 1.17 (95% CI, 1.05–1.29). In a complete case analysis (n= 2147; 44 SCD end points at 5 years), patients with a predicted 5-year risk of Conclusions: This study confirms that the HCM Risk-SCD model provides accurate prognostic information that can be used to target implantable cardioverter defibrillator therapy in patients at the highest risk of SCD.

Hypertrophic cardiomyopathy (HCM) patients present altered myocardial mechanics due to the hypertrophied ventricular wall and are typically diagnosed by the increase in myocardium wall thickness. This study aimed to quantify regional left ventricular (LV) shape, wall stress and deformation from cardiac magnetic resonance (MR) images in HCM patients and controls, in order to establish superior measures to differentiate HCM from controls. A total of 19 HCM patients and 19 controls underwent cardiac MR scans. The acquired MR images were used to reconstruct 3D LV geometrical models and compute the regional parameters (i.e., wall thickness, curvedness, wall stress, area strain and ejection fraction) based on the standard 16 segment model using our in-house software. HCM patients were further classified into four quartiles based on wall thickness at end diastole (ED) to assess the impact of wall thickness on these regional parameters. There was a significant difference between the HCM patients and controls for all regional parameters (P < 0.001). Wall thickness was greater in HCM patients at the end-diastolic and end-systolic phases, and thickness was most pronounced in segments at the septal regions. A multivariate stepwise selection algorithm identified wall stress index at ED (σi,ED) as the single best independent predictor of HCM (AUC = 0.947). At the cutoff value σi,ED < 1.64, both sensitivity and specificity were 94.7%. This suggests that the end-diastolic wall stress index incorporating regional wall curvature—an index based on mechanical principle—is a sensitive biomarker for HCM diagnosis with potential utility in diagnostic and therapeutic assessment.

Hypertrophic cardiomyopathy (HCM) is a genetic disease that leads to left ventricle (LV) hypertrophy with or without the presence of LV outflow tract obstruction. The aim of this study was to find an easy and useful indicator based on cardiac magnetic resonance (CMR) images for control subjects and patients with and without obstruction. CMR scans were performed for 19 control subjects and 19 HCM patients. Endocardial strain was defined as $$S_{\text{endo}} = \left| {{ \ln }\left( {\frac{{L_{{{\text{ES}},\,{\text{endo}}}} }}{{L_{{{\text{ED}},\,{\text{endo}}}} }}} \right)} \right| \times 100\%$$ , with $$L_{{{\text{ED}},\,{\text{endo}}}} \left( {L_{{{\text{ES}},\,{\text{endo}}}} } \right)$$ being the length of endocardium at end-diastole (end-systole); similarly for epicardial strain ( $$S_{\text{epi}}$$ ). The strains were evaluated in cine CMR two-, three- and four-chamber views. Six atrioventricular junction (AVJ) points from three CMR views were semi-automatically tracked. The peak systolic velocity (Sm1), peak early diastolic velocity and late diastolic velocity (Em, Am) were extracted and analysed. Compared with control subjects, HCM patients had significantly smaller three-dimensional strains and AVJ motion incorporating measurements from three long-axis views (all P

As the nonspecific clinical presentation of hypereosinophilic syndrome (HES) may mimic many multisystemic diseases, it often presents as a diagnostic challenge. Herein, we report the case of a 60-year-old man who presented with progressive heart failure symptoms and eosinophilia. Despite extensive diagnostic evaluation, no underlying cause was found. Transthoracic echocardiography revealed a large left ventricular thrombus, which is suggestive of hypereosinophilic cardiac involvement. The patient was started on steroids and responded clinically and haematologically.

Hypertrophic cardiomyopathy (HCM) is the most common hereditary cardiovascular condition. Clinical outcome has been well described but data in South East (SE) Asian population is sparse. We recruited consecutive HCM patients who were seen in our tertiary centre's HCM clinic in a multi-ethnic SE

Introduction: Increasing demand for public healthcare and access to specialist care has become a major concern. Characterising the referral pattern to a national centre’s cardiology specialist outpatient clinics (SOCs) and the diagnostic outcomes may be useful in formulating referral guidelines to contain rising demand. Materials and Methods: A prospective observational follow-up study was conducted of all consecutive new patient referrals to the cardiology SOCs of the National Heart Centre over a 1-month period. The records of these 1224 patients were reviewed following their first visit and again after 3 months of evaluation and investigation. Patients’ demographics, referral sources, indications of referral, risk factors, provisional and final diagnoses were collected. Referrals from the top 2 volume sources (government polyclinics and hospital Emergency Department) accounted for 600 referrals. These subsidised referrals formed the study group for analysis. Results: The mean age of referred patients was 56 ± 15.2 years, with equal proportion of males and females. Most patients had known cardiac risk factors of hypertension (53.2%) and hyperlipidaemia (42.3%). Only 23% of referrals had significant cardiac abnormalities. Referrals for typical chest pain derived the highest yield whereas referrals for atypical chest pain, non-cardiac chest pain derived the lowest yield. Referrals for asymptomatic electrocardiogram (ECG) changes (except for atrial flutter/fibrillation) did not yield cardiac abnormalities. Multivariate analysis of chest pain referrals showed typical chest pain and hyperlipidaemia to be statistically significant predictors for coronary artery disease. Conclusion: Referrals to cardiology outpatient specialist clinics should be based on the presence of patient symptoms, particularly that of typical chest pain. In asymptomatic patients, routine ECG screening did not appear to yield significant cardiac abnormalities. Key words: Diagnostic outcome, Outcome, Referral, Symptoms

Hypertrophic cardiomyopathy (HCM) is a genetic disease that leads to left ventricle (LV) hypertrophy with or without the presence of LV outflow tract obstruction. The aim of this study was to assess endocardial and epicardial strains based on cardiac magnetic resonance (CMR) images for control subjects and patients with and without obstruction. CMR scans were performed for 19 control subjects and 19 HCM patients. Endocardial and epicardial contours were delineated in cine two-, three-, and four-chamber MR images by CMRtools. Endocardial (resp. epicardial) length at end-diastole \(L_\mathrm{{ED,endo}}\) (resp. \(L_\mathrm{{ED,epi}}\)) and end-systole \(L_\mathrm{{ES,endo}}\) (resp. \(L_\mathrm{{ES,epi}}\)) were calculated and endocardial and epicardial strains were defined as S\(_\mathrm{{endo}}=|\ln (L_\mathrm{{ES,endo}}/L_\mathrm{{ED,endo}})|\times 100\%\) and S\(_\mathrm{{epi}}=|\ln (L_\mathrm{{ES,epi}}/L_\mathrm{{ED,epi}})|\times 100\%\), respectively. S\(_\mathrm{{endo}}\) and S\(_\mathrm{{endo}}\) were significantly different between control and HCM patients (both \(P 17.2\%\) had the best sensitivity 94.7\(\%\) and 94.7\(\%\) accuracy to differentiate HCM from normal subjects (AUC = 0.972), and 3-dimensional average endocardial strain \(> 18.8\%\) had the best sensitivity 76.9\(\%\) and 100\(\%\) accuracy to differentiate HCM with and without obstruction (AUC = 0.859). Therefore, 3-dimensional endocardial and epicardial strains may be useful in triage and management of HCM patients with and without obstruction.

Hypertrophic cardiomyopathy (HCM) is a relatively common genetic cardiac disorder in which a portion of the myocardium becomes hypertrophied. Dynamic left ventricle outflow tract obstruction is present and associated with worsened symptom severity and disease progression. However, its mechanism is still not fully understood, and the complex interaction between the thickened ventricular wall and altered blood flow in patient-specific model has not been studied. In this study, we recruited one patient with HCM and one healthy volunteer who underwent magnetic resonance imaging scans. The patient-specific geometries were reconstructed, and both spatial and temporal interpolations were applied to increase the corresponding resolutions. The results showed that HCM patient had cirrostratus-cloud like vortex structures rather than a major vortex ring observed in healthy subject, which implies that the vortex formation from computational fluid dynamics (CFD) simulation has the potential to diagnose HCM.

The patterns of ventricular hypertrophy are critical determinants of blood flow and function, but are variable. Therefore, it is clinically relevant to assess the hypertrophic shape patterns to better characterize and identify the morphological subtypes. We proposed and developed an independent coordinates method (ICM) to quantify the regional shape of the left ventricle in terms of curvature. 19 normal subjects and 5 HCM (hypertrophic cardiomyopathy) patients with different morphological subtype (i.e., septal hypertrophy, mid-ventricular hypertrophy, reverse curvature septum hypertrophy and sigmoid septum hypertrophy) were recruited and underwent magnetic resonance scans. The curvature along the endocardial and epicardial surface was computed using ICM method and was compared in HCM patients against normal subjects. The results showed that curvature plots are variable in different morphological subtype. The curvature pattern demonstrated the utilities in delineating different subtype. In conclusion, ICM method to quantify regional curvature of the left ventricle from magnetic resonance imaging are feasible in normal subjects and those with hypertrophy cardiomyopathy, which may serve as a novel approach to depict local shape of the left ventricle and to assess the morphological subtype in clinical practice.

Percutaneous edge-to-edge mitral valve repair with the MitraClip device has been shown to be effective in reducing the severity of mitral regurgitation (MR), with resultant improvements in clinical outcomes. However, the actual changes in mitral annular geometry has not been well described. We aim