Nonobstructive Hypertrophic Cardiomyopathy Research Articles

3-Dimensional Strain Analysis of Hypertrophic Cardiomyopathy: Insights From the NHLBI International HCM Registry

BackgroundAbnormal global longitudinal strain (GLS) has been independently associated with adverse cardiac outcomes in both obstructive and nonobstructive hypertrophic cardiomyopathy. ObjectivesThe goal of this study was to understand predictors of abnormal GLS from baseline data from the National Heart, Lung, and Blood Institute (NHLBI) Hypertrophic Cardiomyopathy Registry (HCMR). MethodsThe study evaluated comprehensive 3-dimensional left ventricular myocardial strain from cine cardiac magnetic resonance in 2,311 patients from HCMR using in-house validated feature-tracking software. These data were correlated with other imaging markers, serum biomarkers, and demographic variables. ResultsAbnormal median GLS (> –11.0%) was associated with higher left ventricular (LV) mass index (93.8 ± 29.2 g/m2 vs 75.1 ± 19.7 g/m2; P < 0.0001) and maximal wall thickness (21.7 ± 5.2 mm vs 19.3 ± 4.1 mm; P < 0.0001), lower left (62% ± 9% vs 66% ± 7%; P < 0.0001) and right (68% ± 11% vs 69% ± 10%; P < 0.01) ventricular ejection fractions, lower left atrial emptying functions (P < 0.0001 for all), and higher presence and myocardial extent of late gadolinium enhancement (6 SD and visual quantification; P < 0.0001 for both). Elastic net regression showed that adjusted predictors of GLS included female sex, Black race, history of syncope, presence of systolic anterior motion of the mitral valve, reverse curvature and apical morphologies, LV ejection fraction, LV mass index, and both presence/extent of late gadolinium enhancement and baseline N-terminal pro–B-type natriuretic peptide and troponin levels. ConclusionsAbnormal strain in hypertrophic cardiomyopathy is associated with other imaging and serum biomarkers of increased risk. Further follow-up of the HCMR cohort is needed to understand the independent relationship between LV strain and adverse cardiac outcomes in hypertrophic cardiomyopathy.

Efficacy of SGLT2 Inhibitors in Patients With Diabetes and Nonobstructive Hypertrophic Cardiomyopathy

The objective of this study was to evaluate the effects of sodium glucose co-transporter 2 inhibitors (SGLT2i) on functional capacity and diastolic function in patients with diabetes with nonobstructive hypertrophic cardiomyopathy (nHCM) and preserved left ventricular (LV) function. From January 2019 to October 2020, a prospective open-label study was performed on patients with type 2 diabetes mellitus and nHCM with New York Heart Association class II-III symptoms. Patients with a LV ejection fraction <50% were excluded. Patients were recruited from January 2019 to November 2019 to the SGLT2i arm and from November 2019 to October 2020 to the control arm. The primary composite end point was defined as achieving an improvement of at least 1.5 in E/e' and a reduction of ≥1 New York Heart Association functional class after 6months of therapy. At baseline, there were no significant differences between the SGLT2i (n=24) and control arms (n=24). More patients in the SGLT2i arm achieved the primary end point than the patients in the control arm (70.8% vs 4.2%, p <0.001). After 6months of therapy, patients in the SGLT2i arm showed a significant improvement in all diastolic function parameters (E/e' 16.3 ± 1.9 vs 13.3 ± 1.6, p <0.001; E/A 2.8 ± 0.1 vs 2.4 ± 0.1, p <0.001; left atrial volume 45.6 ± 5.2 vs 40.8 ± 4.9ml/m2, p=0.003). There was also an improvement in the 6-minute walk distance (295.1 ± 31.5 vs 343.0 ± 31.1m, p <0.001) and N-terminal pro-B-type natriuretic peptide (481.4 ± 52.6 vs 440.9 ± 43.9pg/ml, p <0.001) in patients who received SGLT2i. There was no significant change in the LV mass in the SGLT2i or control arm (-0.1 ± 0.3 vs 0.1 ± 0.5g/m2, p=0.319) after 6months of therapy. A patient in the SGLT2i arm discontinued therapy because of a urinary tract infection. In conclusion, the use of SGLT2i improved diastolic function and functional capacity in patients with diabetes with nHCM and a preserved LV function.

Abstract 12690: Mavacamten Treatment in Patients With Obstructive and Nonobstructive Hypertrophic Cardiomyopathy: A Pooled Safety Analysis of 5 Clinical Trials

Introduction: Mavacamten, a cardiac myosin inhibitor, is approved by the US FDA for the treatment of adults with symptomatic obstructive HCM. We present results from an integrated analysis of pooled mavacamten safety data from clinical studies in patients (pts) with obstructive and nonobstructive HCM. Methods: Pts who received ≥1 dose of mavacamten in phase 2 and 3 studies (PIONEER-HCM [end of study date: Jan 12, 2018]; MAVERICK-HCM [Jan 7, 2020]; EXPLORER-HCM [Jul 1, 2020]) and ongoing extension studies (PIONEER-OLE and MAVA-LTE [data cut-off date: Aug 31, 2021]) comprised the pooled analysis population. Results: Data were pooled from a total of 314 unique pts with obstructive (n=260) or nonobstructive (n=54) HCM. Baseline characteristics are shown in the Table. Cumulative time on study (parent + extension) was ≥6 mo for 91% of pts. The mean cumulative duration of mavacamten exposure was 20.2 mo (range: 0.3, 42.5; median: 20.7 mo); 5.4% of pts permanently discontinued treatment due to treatment-emergent adverse events (TEAEs). Total cumulative exposure was 527.6 pt-yrs, and the median average daily dose of mavacamten was 5.7 mg. Generally similar proportions of pts on mavacamten vs placebo experienced grade ≥3, serious, or drug-related TEAEs; few pts experienced TEAEs that led to study discontinuation or drug interruption ( Table ). The exposure-adjusted incidence of adjudicated events in EXPLORER-HCM and MAVA-LTE of heart failure and new-onset atrial fibrillation were 1.42 and 3.07 per 100 pt-yrs, respectively. As previously reported, 4 deaths occurred across studies: 3 in the mavacamten arm due to TEAEs (bacterial endocarditis, cardiac arrest, and acute myocardial infarction [all, n=1]), with none considered related to study drug, and 1 in the placebo arm (sudden death). Conclusion: Integrated evaluation of existing trial data in HCM show that mavacamten is safe and generally well tolerated, irrespective of the presence of obstruction and across multiple doses.

Abstract 14023: Myocardial Perfusion Abnormalities: A Potential Biomarker for Ventricular Arrhythmias in Hypertrophic Cardiomyopathy Young Patients?

Introduction: Despite progress in the field, risk stratification for sudden death in patients with hypertrophic cardiomyopathy (HCM) remains challenging. Although ventricular arrhythmias (VA) account for most of these events, the mechanisms responsible for cardiac arrest in HCM are not understood. Hypothesis: Abnormalities in myocardial perfusion may create an arrhythmogenic substrate in HCM patients. Methods/ Results: A 12-year-old boy was admitted to our department after an out-of-hospital cardiac arrest, with documented ventricular fibrillation while running. A non-obstructive asymmetric HCM was diagnosed with echocardiography (max LV wall thickness 32 mm). He had one conventional risk factor for SCD. Genetic testing revealed a heterozygous state for a MYH7 variation: p.Glu500Ala (NM_000257.3:c.1499A&gt;C). This variation was classified as “probably pathogenic” (class 4 according to ACMG). His father and his 15-year-old brother were heterozygous for the same variant and were asymptomatic. The brother displayed a similar HCM phenotype. The patient received an implantable defibrillator and suffered from appropriate exercise-related shocks within 6-months despite sotalol therapy (160 mg bid). Because the VA occurred always when the patient was engaged in vigorous physical activity despite beta blocker and since he could not refrain from physical activity, thallium-201 myocardial scintigraphy was performed. To further understand the arrhythmogenic phenotype, his brother underwent the same investigation. Significant uptake perfusion defects in both initial and delayed images were evident in the proband (15%) but not in the asymptomatic brother. Treatment with antianginal drug (amlodipine 5 mg/day) was initiated. With 10 mg/day amlodipine was associated with a significant improvement of the scintigraphy (6% versus 15% perfusion defect). At a follow-up of 12 months, there was no recurrence of VA. Conclusions: Regarding HCM patients, the present report 1) strengthens the hypothesis that myocardial perfusion defects may identify patients at risk for VA, 2) suggests that tailored anti-ischemic prescription may be useful, and 3) underscores the need of prospective studies quantifying ischemia in HCM patients with exercise-induced VF.

Severe Septal Hypertrophy in a Young Asymptomatic Female

Hypertrophic cardiomyopathy is the most common cause of death in young people, with a ratio of 1/500 in the general population, whilst focal left ventricular thickening with no family history is rare. This 23-year-old female presented with asymptomatic severe concentric hypertrophy of an unknown source, suspected to be caused by cardiomyopathy. The echocardiogram showed a severely thickened septal and anterolateral wall consistent with non-obstructive hypertrophic cardiomyopathy (HCM); there is no known family history of cardiomyopathies, and upon further investigation of the echocardiographic images, the thickening appeared analogously with a cardiac tumor in the septal wall rather than cardiomyopathy. The differential diagnosis, in this case, was that there was a non-obstructive HCM, but that further imaging would be required for confirmation. This case emphasizes the importance of conducting an echocardiogram on all patients with abnormal electrocardiograms regardless of their symptomology.

Contemporary Therapies and Future Directions in the Management of Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by pathogenic variants in sarcomeric genes, leading to left ventricular hypertrophy and complex phenotypic heterogeneity. While HCM is the most common inherited cardiomyopathy, pharmacological treatment options have previously been limited and were predominantly directed towards symptom control owing to left ventricular outflow obstruction. These therapies, including beta blockers, calcium channel blockers, and disopyramide, have not been shown to affect the natural history of the disease, which is of particular concern for younger patients who have an increased lifetime risk of experiencing arrhythmias, heart failure, and sudden cardiac death. Increased knowledge of the genetic mechanisms underlying this disease in recent years has led to the development of targeted, potentially disease-modifying therapies for both obstructive and nonobstructive phenotypes that may help to prevent or ameliorate left ventricular hypertrophy. In this review article, we will define the etiology and clinical phenotypes of HCM, summarize the conventional therapies for obstructive HCM, discuss the emerging targeted therapies as well as novel invasive approaches for obstructive HCM, describe the therapeutic advances for nonobstructive HCM, and outline the future directions for the treatment of HCM.

Subtypes and Mechanisms of Hypertrophic Cardiomyopathy Proposed by Machine Learning Algorithms.

Hypertrophic cardiomyopathy (HCM) is a relatively common inherited cardiac disease that results in left ventricular hypertrophy. Machine learning uses algorithms to study patterns in data and develop models able to make predictions. The aim of this study is to identify HCM subtypes and examine the mechanisms of HCM using machine learning algorithms. Clinical and laboratory findings of 143 adult patients with a confirmed diagnosis of nonobstructive HCM are analyzed; HCM subtypes are determined by clustering, while the presence of different HCM features is predicted in classification machine learning tasks. Four clusters are determined as the optimal number of clusters for this dataset. Models that can predict the presence of particular HCM features from other genotypic and phenotypic information are generated, and subsets of features sufficient to predict the presence of other features of HCM are determined. This research proposes four subtypes of HCM assessed by machine learning algorithms and based on the overall phenotypic expression of the participants of the study. The identified subsets of features sufficient to determine the presence of particular HCM aspects could provide deeper insights into the mechanisms of HCM.

Estimating the prevalence, clinical characteristics, and treatment patterns of hypertrophic cardiomyopathy in Japan: A nationwide medical claims database study

BackgroundLimited data are available regarding therapies for hypertrophic cardiomyopathy (HCM). This study assessed the prevalence, clinical characteristics, and treatment patterns of HCM in Japan. MethodsThis retrospective database study analyzed data from 438 hospitals in the Japan Medical Data Vision database from 2016 to 2020. We identified 3913 patients (15 %) with obstructive HCM (oHCM) and 21,714 patients (85 %) with nonobstructive HCM (nHCM). ResultsThe estimated total number of patients with oHCM and nHCM in 2020 among Japanese hospitals was 8500 and 43,500, respectively. The prevalence of oHCM and nHCM steadily increased by 27 % and 12 %, respectively, from 2016 to 2020, with a 1:5.2 ratio of oHCM to nHCM in 2020. The mean age of the oHCM and nHCM populations was 72 and 70 years, respectively, and comorbidities included atrial fibrillation (AF) (oHCM, 33.8 %; nHCM, 32.2 %), other arrythmia (30.1 %; 27.6 %), and stroke (16.6 %; 16.4 %). Furthermore, 45.0 % of oHCM and 37.7 % of nHCM patients had undergone at least one hospitalization. A substantial number of HCM patients aged between 20 and 59 years reported AF (oHCM, 17–37 %; nHCM, 4–24 %) and stroke (oHCM, 0–12 %; nHCM, 3–10 %). β-blockers (oHCM, 64.0 %; nHCM, 42.1 %) were the most frequently prescribed treatment, followed by Na channel blockers (29.5 %; 5.7 %), calcium channel blockers (18.1 %; 8.8 %), direct oral anticoagulants (14.5 %; 15.2 %), and warfarin (11.0 %; 11.4 %). ConclusionsThis study provides important information on the current epidemiological and clinical characteristics of HCM in Japan.

Population estimates of obstructive and non-obstructive hypertrophic cardiomyopathy in the UK and Germany

Abstract Background While numerous publications have estimated the prevalence of diagnosed hypertrophic cardiomyopathy (HCM), none have quantified the real-world proportion of obstructive and non-obstructive HCM using nationally representative data sources in any European countries. Purpose To estimate the prevalence of diagnosed HCM and its subtypes in the UK and Germany. Methods Patients with HCM were identified in the UK from 01 Apr 2009 to 30 Oct 2020 and Germany from 2011 to 2019. UK patients with HCM were identified using electronic health records from the Clinical Practice Research Datalink (CPRD) primary care data linked with Hospital Episode Statistics (HES) secondary care data using ICD-10 (I42.1, I42.2), Read, Medcode, SNOMED, and OPCS codes. German patients with HCM were identified using a nationally representative administrative claims data pool (WIG2 Benchmark database) from several German Statutory Health Insurance (SHI)-insurances using ICD-10 and OPS codes. Obstructive HCM was identified as any obstructive HCM diagnosis, any HCM diagnosis with septal reduction therapy, and any HCM diagnosis and left ventricular outflow tract obstruction (LVOTO; not in German claims data). Non-obstructive HCM was any non-obstructive or unspecified HCM diagnosis without evidence of any obstructive HCM. Annual prevalence was calculated for each year in the respective study periods and average annual prevalence across the study period. Results The average annual prevalence rate of HCM was 4.15/10,000 in the UK and 8.61/10,000 in Germany, while the average annual prevalence rate of obstructive HCM was 2.84/10,000 in the UK and 4.18/10,000 in Germany (Table). The proportion of HCM that was obstructive HCM was 68% in the UK and 49% in Germany. The prevalence rates of diagnosed HCM and obstructive HCM tended to increase over time (Figure). Conclusion The prevalence of HCM, obstructive HCM and the proportion of HCM that is obstructive varied between the UK and Germany. The prevalence of HCM was generally consistent with previously published estimates. Although there are limitations with coding in administrative data, it is important to differentiate obstructive HCM from non-obstructive HCM given their unique treatments and disease progression and management, especially since at least 49–68% of HCM is obstructive. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bristol Myers-Squibb

Microvascular dysfunction is associated with impaired myocardial work in obstructive and nonobstructive hypertrophic cardiomyopathy: a multimodality approach

Abstract Introduction Myocardial work is a dynamic non-invasive method for assessing myocardial deformation. Microvascular dysfunction is a hallmark of hypertrophic cardiomyopathy (HCM). We hypothesized that there is an association between impaired myocardial work, evaluated by echocardiography, and left ventricular (LV) ischemia, detected by cardiac magnetic resonance (CMR). Methods Prospective assessment of HCM patients' (P) myocardial strain parameters with 2D speckle-tracking echocardiography. All P underwent CMR protocol (1.5-T) for the analysis of stress perfusion and late gadolinium enhancement (LGE). Perfusion defects were quantified as burden of ischemia (% of LV mass). Results were stratified according to obstructive (oHCM) and nonobstructive (nHCM) HCM as well as according to the presence of significant replacement fibrosis (LGE of ≥15% or &amp;lt;15% of LV mass). Multivariate regression analyses were used to explore the relation between myocardial work and the burden of ischemia. Results 75 P with HCM (63% male, age 55±15 years), 61% with asymmetric septal LVH, 29% with apical LVH, 8% with concentric LVH and 28% exhibiting LV outflow tract obstruction (mean maximal LVOT gradient of 89±60 mmHg). Perfusion defects were found in 68 P (90.7%), with a mean of 22.5±16.9% of LV mass and 29 P (38.7%) had LGE ≥15% of LV mass. A lower global work index (GWI) significantly correlated with higher burden of myocardial perfusion defects (r=−0.520, β-estimate −0.019, 95% CI −0.028 to −0.010, p&amp;lt;0.001). Likewise, impaired values of global work efficiency (GWE) were linked to higher percentage of hypoperfusion (r=−0.477, β-estimate −0.713, 95% CI −1.250 to −0.176, p&amp;lt;0.001). Moreover, impaired global constructive work (GCW) (r=−0.519, β-estimate −0.021, 95% CI −0.030 to −0.013, p&amp;lt;0.001) and a higher global wasted work (GWW) (r=0.280, p=0.017) were associated with a higher burden of perfusion defects (Figure 1). GWI showed a higher correlation with perfusion defects in oHCM P (r=−0.518, p=0.019) vs. nHCM P (r=−0.492, p&amp;lt;0.001), and the same was also found with GWE (oHCM: r=−0.591, p=0.006 vs. nHCM: r=−0.317, p=0.022) (Figure 2A). Furthermore, GCW showed a slightly higher correlation with hypoperfusion in oHCM P (r=−0.564, p=0.010) vs. nHCM P (r=−0.520, p&amp;lt;0.001). There was no significant difference between oHCM and nHCM P regarding GWW. In P with LGE ≥15%, GWI showed a better correlation with perfusion defects (r=−0.489, p=0.007) vs. P with LGE of &amp;lt;15% (r=−0.369, p=0.007). Moreover, GCW showed a higher correlation with hypoperfusion in P with LGE ≥15% (r=−0.455, p=0.013) comparing with P with LGE &amp;lt;15% LV mass (r=−0.359, p=0.019) (Figure 2B). No difference was found regarding GWE and GWW according to LGE burden. Conclusion In our cohort of P with HCM, impaired GWI, GWE and GCW and a higher GWW were significantly correlated with the presence of myocardial ischemia in CMR. This correlation was greater in P with oHCM and in P with LGE of ≥15% of LV mass. Funding Acknowledgement Type of funding sources: None.

Temporal trends, characteristics and comorbidities of patients with hypertrophic cardiomyopathy in Denmark from 2005 to 2018: a nationwide cohort study

Abstract Background The majority of patients with Hypertrophic cardiomyopathy (HCM) are mildly symptomatic or unaware of their condition, but some develop serious complications such as heart failure, atrial fibrillation (AF) as well as sudden cardiac death. Previous studies have suggested that HCM detection-rates in women are significantly lower than in men. This leads to diagnosis often being delayed to later stages of the disease in women, where symptoms are more severe. Further characterization of HCM patients to improve early detection of adverse outcomes and warning signs might improve long-term outcomes. Purpose To describe the characteristics of Danish patients diagnosed with HCM between 2005–2018 and determine trends and changes in these factors over time. Methods All patients aged 16 years or older with a diagnosis of HCM between the 1st of January 2005 and the 31st of December 2018 were identified in Danish nationwide administrative registers and included in the study. Time trends were calculated, and differences analyzed using the Cochran-Armitage trend test and linear regression. Results A total of 3856 patients were diagnosed with HCM in the study period and included in the study. The median age at diagnosis was 68 years (IQR 56 and 78 years), 53% were male, and 44% were diagnosed with obstructive HCM, while the number of patients diagnosed with HCM each year overall increased. At the time of diagnosis, 22,3% patients were previously diagnosed with ischemic heart disease, 17% with AF, 7,5% with ischemic stroke, 13,6% with heart failure. Median age and gender distribution remained stable over time, while the proportion of obstructive HCM among the newly diagnosed decreased (p = &amp;lt;0.001) (Figure1). During the study period, there was a significant decrease in the prevalence of heart failure (p = &amp;lt;0.001), ischemic heart disease (p = &amp;lt;0.001), and chronic obstructive pulmonary syndrome (p = &amp;lt;0.001), while the prevalence of AF, hypertension and ischemic stroke remained stable (Figure 2). Conclusion Despite previous studies describing a gender gap in patients diagnosed with HCM, gender distribution was near equal in this cohort. The number of patients diagnosed with non-obstructive HCM is increasing and the prevalence of comorbidities such as heart failure, ischemic heart disease, and COPD decreased over time. Whether these findings are the result of improved early detection of HCM warrants further research and examination. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Herlev-Gentofte Hospital, Denmark

Predictors of left ventricular dysfunction in hypertrophic cardiomyopathy: results from a nationwide registry

Abstract Introduction Progression of hypertrophic cardiomyopathy (HCM) with incident left ventricular (LV) dysfunction (HCM-LVSD) is associated with poor prognosis and advanced heart failure (HF). Prevalence ranges from 5–10% in previous studies. Identification of predictors of adverse remodeling may improve risk stratification and prognostication in HCM. Purpose To identify predictors of HCM-LVSD in a nationwide cohort of HCM patients (pts). Methods Retrospective study including all HCM pts enrolled in a European country-based nationwide registry. HCM-LVSD group included pts with LV ejection fraction (LVEF) ≤50% at baseline and pts who developed LV dysfunction/dilated phenotype during follow-up. Multivariate logistic regression was performed to identify predictors of HCM-LVSD. Results 1042 HCM patients (57.8% male, mean age at diagnosis 52 years) were included, of whom 81 (8%) belonged to the HCM-LVSD group. HCM-LVSD pts were mostly male (60.5%) and tended to be older at the time of diagnosis than those without LVSD (55 vs 52 years, p=0.054). HCM-LVSD pts were more often symptomatic at the index visit (84.1% vs 65.2%, p&amp;lt;0.001), with more functional impairment (New York Heart Association class III–IV: 18.5% vs 9.2%, p=0.021). Atrial fibrillation (21.3% vs 8.6%, p&amp;lt;0.001) and intraventricular conduction disturbances (28.6% vs 14.4%, p=0.002) were more prevalent in HCM-LVSD pts. HCM-LVSD pts had higher baseline left atrium (LA) volumes (52 vs 39 ml, p=0.001), lower LVEF (50 vs 67%, p&amp;lt;0.001) and higher rates of mitral regurgitation (79.0% vs 65.1%, p=0.011). Prevalence of obstructive HCM was lower in the HCM-LSVD group (25.3% vs 40.9%, p=0.007). Presence of late gadolinium enhancement (92.6% vs 74.6%, p=0.035) was more common in pts with LVSD. Baseline N-terminal pro–B-type natriuretic peptide was higher in HCM-LVSD (3839 vs 1281 pg/ml, p=0.027). There were no differences in the number and type of genetic variants between groups. In HCM-LVSD pts, implantation of cardioverter-defibrillators for secondary prevention was more frequent (28.6% vs 6.4%, p=0.002), as was the use of pacemaker (16.7% vs 7.0%, p=0.002). During a mean follow-up of 5.3±6.1 years, hospitalization for HF (50.0% vs 11.3%) and all-cause mortality (12.3% vs 2.9%, p&amp;lt;0.001) were more frequent in HCM-LVSD group. After multivariate analysis, higher LA volume (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01–1.05, p=0.003) and nonobstructive HCM (OR 2.74, 95% CI 1.03–7.27, p=0.043) were independent predictors of HCM-LVSD. Conclusions In this large nationwide cohort of HCM pts, prevalence of LVSD was 8%, in line with existing literature. In this cohort, larger LA volumes and nonobstructive HCM predicted progression to HCM-LVSD. Funding Acknowledgement Type of funding sources: None.

Novel biomarkers identifying hypertrophic cardiomyopathy and its obstructive variant based on targeted amino acid metabolomics.

Hypertrophic cardiomyopathy (HCM) is an underdiagnosed genetic heart disease worldwide. The management and prognosis of obstructive HCM (HOCM) and non-obstructive HCM (HNCM) are quite different, but it also remains challenging to discriminate these two subtypes. HCM is characterized by dysmetabolism, and myocardial amino acid (AA) metabolism is robustly changed. The present study aimed to delineate plasma AA and derivatives profiles, and identify potential biomarkers for HCM. Plasma samples from 166 participants, including 57 cases of HOCM, 52 cases of HNCM, and 57 normal controls (NCs), who first visited the International Cooperation Center for HCM, Xijing Hospital between December 2019 and September 2020, were collected and analyzed by high-performance liquid chromatography-mass spectrometry based on targeted AA metabolomics. Three separate classification algorithms, including random forest, support vector machine, and logistic regression, were applied for the identification of specific AA and derivatives compositions for HCM and the development of screening models to discriminate HCM from NC as well as HOCM from HNCM. The univariate analysis showed that the serine, glycine, proline, citrulline, glutamine, cystine, creatinine, cysteine, choline, and aminoadipic acid levels in the HCM group were significantly different from those in the NC group. Four AAs and derivatives (Panel A; proline, glycine, cysteine, and choline) were screened out by multiple feature selection algorithms for discriminating HCM patients from NCs. The receiver operating characteristic (ROC) analysis in Panel A yielded an area under the ROC curve (AUC) of 0.83 (0.75-0.91) in the training set and 0.79 (0.65-0.94) in the validation set. Moreover, among 10 AAs and derivatives (arginine, phenylalanine, tyrosine, proline, alanine, asparagine, creatine, tryptophan, ornithine, and choline) with statistical significance between HOCM and HNCM, 3 AAs (Panel B; arginine, proline, and ornithine) were selected to differentiate the two subgroups. The AUC values in the training and validation sets for Panel B were 0.83 (0.74-0.93) and 0.82 (0.66-0.98), respectively. The plasma AA and derivatives profiles were distinct between the HCM and NC groups. Based on the differential profiles, the two established screening models have potential value in assisting HCM screening and identifying whether it is obstructive.

Prevalence and influence of pulmonary hypertension in patients with obstructive hypertrophic cardiomyopathy undergoing septal myectomy

ObjectivesPulmonary hypertension (PH) is an independent predictor of all-cause mortality among patients with obstructive and nonobstructive hypertrophic cardiomyopathy (HCM). However, there is little information on the influence of coexisting PH on long-term survival following septal myectomy. This study investigates the prevalence of PH among patients with obstructive HCM undergoing septal myectomy and analyzes patient survival and the course of PH after operation. MethodsWe included 1342 patients with obstructive HCM who had Doppler echocardiographic estimates of the right ventricular systolic pressure (RVSP) before and after transaortic septal myectomy. PH was defined as RVSP ≥35 mm Hg, with ≥50 mm Hg categorized as moderate-to-severe PH. A multivariable Cox proportional hazards model was used to identify characteristics associated with survival, and longitudinal trends in RVSP were modeled with generalized least squares analysis. ResultsPatients underwent operations from 1989 to 2019. The median age was 57.9 years (interquartile range, 47.4-66.7 years); 49.5% were women. Preoperatively, PH was present in 47.8% of patients, and 14.4% had moderate-to-severe PH. Higher preoperative RVSP was independently associated with overall mortality in the multivariable Cox model. Among patients with moderate to severe preoperative RVSP elevation, postoperative RVSP decreased from baseline by a median of 12 mm Hg. ConclusionsPreoperative PH is independently associated with late mortality following septal myectomy, and the magnitude of preoperative RVSP was associated with a postoperative decrease in pulmonary pressure. The influence of PH on late postoperative survival may influence the timing of operation in patients who are candidates for septal myectomy.

Mavacamten, a First-in-Class Cardiac Myosin Inhibitor for Obstructive Hypertrophic Cardiomyopathy.

To assess mavacamten's role in hypertrophic cardiomyopathy treatment. In addition to clinical guidelines, package inserts, and general reviews, we searched PubMed using the term mavacamten from inception to June 11, 2022. English language studies describing mavacamten's mechanism of action, pharmacokinetics, drug interactions, clinical and economic outcomes, and adverse events. Mavacamten reduces left ventricular outflow obstruction and New York Heart Association functional class while improving Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores in patients with obstructive hypertrophic cardiomyopathy. With an acquisition cost of $245.20 per capsule, it would cost $1.2 million for every additional quality-adjusted life year. In those with unobstructive hypertrophic cardiomyopathy, there were improvements in N-terminal probrain natriuretic peptide and high-sensitivity cardiac troponin biochemical markers. Mavacamten is a substrate for CYP2C19 and CYP3A4, and a CYP enzyme inducer. Patients with obstructive hypertrophic cardiomyopathy and an ejection fraction ≥55% have a new option if they remain symptomatic despite maximally tolerated β-blocker or non-dihydropyridine calcium channel blocker therapy. It is an alternative to disopyramide therapy, which has poor patient tolerance, or septal reduction therapies, which are invasive. However, mavacamten is not cost-effective and its role in nonobstructive hypertrophic cardiomyopathy is not well established. Mavacamten is a new option for patients with refractory obstructive hypertrophic cardiomyopathy and an ejection fraction ≥55% but its pricing makes therapy not cost-effective. Final health outcomes are not fully elucidated and additional studies are needed to determine long-term effects.

Evaluation of Exercise Tolerance in Non-obstructive Hypertrophic Cardiomyopathy With Myocardial Work and Peak Strain Dispersion by Speckle-Tracking Echocardiography.

BackgroundThe aim of this study was to evaluate exercise tolerance in non-obstructive hypertrophic cardiomyopathy (HCM) by investigating the value of myocardial work (MW) combined with strain peak dispersion.MethodsA total of 65 patients with non-obstructive HCM and normal left ventricular ejection fraction were enrolled and 60 healthy subjects were selected as controls. The automated function imaging (AFI)-two-dimensional ultrasonic speckle-tracking technology was used to obtain the values for peak global longitudinal strain (GLS), longitudinal strain peak time dispersion (PSD), 18-segment systolic longitudinal peak strain (LPS), 18-segment longitudinal strain peak time (TTPLS), global waste work (GWW), global constructive work (GCW), global work index (GWI), global work efficiency (GWE), and exercise metabolic equivalents (METS).Results(1) Values for LV-GLS (−17.77 ± 0.20 vs. −21.66 ± 0.42%) were lower and PSD (95.10 ± 8.15 vs. 28.97 ± 1.50 ms) was prolonged in patients with HCM (p < 0.01). (2) An increasing trend was shown in the basal segment < intermediate segment < apical segment for both patients with HCM and controls, although each segment had lower values in the HCM group. (3) TTPLS was prolonged in the HCM group (p < 0.01). (4) GWE, GWI, and GCW were all lower (p < 0.01) and GWW was higher in patients with HCM (p < 0.01). (5) Values of GWE were less than 92.5%, GWI less than 1,200 mmHg, GCW less than 1,399 mmHg, these abnormal values are helpful for the diagnosis of impaired exercise tolerance and poor prognosis (6) The METS and LV-GLS of HCM in the asymmetric group were significantly lower than that in AHCM group, but the PSD was significantly greater than that in the AHCM group. Values of LPS-BL (−13.13% ± 2.51% vs −10.17% ± 2.20%) in the apical HCM group were better than in the asymmetric HCM group (p < 0.05).ConclusionGCW, GWI, and GWE can be safely measured by resting echocardiography to evaluate exercise tolerance in patients with HCM who cannot perform an exercise-based examination. Such measurements provide a basis for clinical decisions regarding exercise and drug prescription.

Index of microcirculatory resistance in the assessment of coronary microvascular dysfunction in hypertrophic cardiomyopathy

Introduction and objectivesCoronary microvascular dysfunction (CMD) is one of the most important pathophysiological features in hypertrophic cardiomyopathy (HCM). The index of microcirculatory resistance (IMR) is an invasive method to assess the coronary microcirculation. The aim was to assess CMD in patients with HCM by IMR. MethodsAdult patients with HCM without epicardial coronary artery disease underwent cardiac catheterization for the assessment of CMD by IMR (normal cut-off value ≤22.0) and coronary flow reserve (CFR) (normal cut-off value ≥2). Cardiovascular magnetic resonance (CMR) was performed to assess the ischemic burden by perfusion imaging during regadenoson-induced hyperemia, and the extent of myocardial fibrosis was assessed by late gadolinium enhancement (LGE), native T1 mapping and extracellular volume (ECV). ResultsFourteen patients were enrolled with a mean age of 62.8±6.2years, 8 (57.1%) males, of whom 9 (64.3%) had obstructive HCM. Using IMR, CMD was detected in 4 (29%) patients. Among four patients with an IMR>22.0, all had non-obstructive HCM and two had angina. CFR<2 was reported in eight patients (57%). Concordance between IMR and CFR (both normal or both abnormal) was verified in 6 patients (43%). Among four patients with IMR>22.0, perfusion defects were found in two of the three patients who underwent stress CMR. Increased ECV (>28%) was documented in two of the patients with IMR>22 and in three of the patients with IMR≤22.0. LGE was >15% in 2 of the patients with IMR>22 and in 4 with IMR≤22.0. ConclusionsIMR assessment in HCM is feasible and safe. Patients with abnormal IMR seemed to have more significant tissue abnormalities on CMR.

Ventricular Septal Myectomy Decreases Long-Term Risk for Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy

Atrial fibrillation (AF) is the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM) and is an important cause of morbidity and embolic stroke. The impact of outflow obstruction and the influence of surgical septal myectomy on the development of new-onset AF has not been well described. Consecutive patients with HCM without previous AF were followed for 5.0 ± 3.6years for new-onset AF, including 717 with obstruction who did not undergo surgical myectomy (outflow gradients ≥30mm Hg at rest or after provocation), 555 with nonobstructive HCM (outflow gradients &lt;30mm Hg), and 503 who underwent surgical myectomy. Patients with obstructive HCM who did not undergo myectomy had a 1.5-fold increased risk for new-onset AF compared with nonobstructive HCM (26% vs 16% at 10years, hazard ratio = 0.69, p=0.02). Patients who underwent myectomy had more advanced heart failure (95% vs 18% New York Heart Association class III, p &lt;0.001) and had larger left atrium dimension (42±7 vs 41±7mm; p &lt;0.01) as compared with patients with obstructive HCM who did not undergo myectomy. However, after myectomy, the risk of new-onset AF was significantly lower than nonoperated obstructive (17% vs 26% at 10years, p=0.04) and no different from the risk of AF in patients with nonobstructive HC (hazard ratio 0.95, p=0.81).In conclusion, patients with HCM with outflow obstruction are at a higher risk for AF compared with patients with nonobstructive HCM. However, after surgical myectomy, the risk for new-onset AF is substantially reduced. In addition to the known benefits of myectomy to permanently relieve outflow tract obstruction and mitral regurgitation, reverse heart failure symptoms, and increase longevity, myectomy is now shown to decrease susceptibility to AF in HCM.

The value of myocardial work in assessment of ventricular function in patients with non-obstructive hypertrophic cardiomyopathy

BackgroundTo evaluate myocardial work using speckle tracking echocardiography in patients with non-obstructive hypertrophic cardiomyopathy (HCM).MethodsFifty patients with HCM and 50 normal controls were included. Left ventricular ejection fraction (LVEF) was quantified using the bi-plane Simpson’s method. Myocardial work parameters, which included global work index (GWI), global constructive work (GCW), global waste work (GWW), and global work efficiency (GWE), were derived from the 2D strain-pressure loop.ResultsThe patient group was older (49.19 ± 14.69 vs. 37.16 ± 7.49 years old) and had a higher body mass index (24.93 ± 3.67 vs. 23.26 ± 3.32 kg/m2) and systolic blood pressure (121.81 ± 16.50 vs. 115.30 ± 11.01 mmHg) (P < 0.05). The mean LVEF in patients was 51%, with 54% of patients had LVEF ≤ 50%. Compared to controls, GWI (946.42 ± 360.64 vs. 1639.72 ± 204.56 mmHg%), GCW (1176.94 ± 373.23 vs. 1960.16 ± 255.72 mmHg%), and GWE (83.96 ± 7.68 vs. 95.26 ± 1.98%) were significantly decreased, while GWW (158.17 ± 82.47 vs. 79.12 ± 40.26 mmHg%) was significantly increased (P < 0.05) in the patient group. In patients, GWE showed a trend of positive correlation with LVEF (r = 0.276, P = 0.06), while GWW had a trend of negative correlation with LVEF (r = − 0.241, P = 0.09). No correlation between myocardial work and LV diastolic function or QRS duration was observed. Maximal wall thickness significantly correlated with all the myocardial work parameters.ConclusionsAssessing myocardial work adds useful information of LV function in patients with non-obstructive HCM.

Exercise-induced pulmonary hypertension in hypertrophic cardiomyopathy: a combined cardiopulmonary exercise test-echocardiographic study.

Pulmonary arterial hypertension (PAH), documented in a significant portion of hypertrophic cardiomyopathy (HCM) patients, has been shown to adversely impact prognosis. In most HCM patients congestive symptoms are consistently elicited by exercise, thus suggesting the need for a provocative test to assess cardiac hemodynamics during effort. Combining cardiopulmonary exercise test (CPET) with echocardiography, we aimed to evaluate the presence of exercise induced pulmonary arterial hypertension (EiPAH), its role in functional limitation and its prognostic significance in a cohort of patients with obstructive and non-obstructive HCM. Study population included 182 HCM patients evaluated combining CPET and stress echocardiography. Left-ventricular outflow tract (LVOT) velocities, trans-tricuspid gradient, and cardiopulmonary variables were continuously measured. Thirty-seven patients (20%) developed EiPAH, defined as systolic pulmonary arterial pressure (sPAP) > 40mmHg during exercise. EiPAH was associated with lower exercise performance, larger left atrial volumes, higher LVOT gradient and higher VE/VCO2 slope. At multivariable analysis baseline sPAP (p < 0.0001) and baseline LVOT obstruction (p = 0.028) were significantly associated with EiPAH. Kaplan-Meier curve analysis showed EiPAH was a significant predictor of HCM-related morbidity (Hazard Ratio 6.21, 95% CI 1.47-26.19; p = 0.05; 4.21, 95% CI 1.94-9.12; p < 0.001 for the primary and the secondary endpoint respectively). EiPAH was present in about one fifth of HCM patients without evidence of elevated pulmonary pressures at rest and was associated with adverse clinical outcome. Diagnosing EiPAH by exercise echocardiography/CPET may help physicians to detect early stage of PAH thus allowing a closer clinical monitoring and individualized therapies.