Diagnosis Of Hypertrophic Cardiomyopathy Research Articles

751 CANCER TREATMENT RELATED COMPLICATIONS IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY

Abstract Introduction Cardiotoxicity involves direct effects of cancer related treatment on heart function, commonly presenting as left ventricular contractile dysfunction. However, limited data are available regarding cardiotoxicity on hypertrophic cardiomyopathy (HCM), because most studies and registries have not specifically analyzed the effects of oncological treatment in HCM populations. This gap in knowledge may lead to unjustified restriction of HCM patients to radical cancer treatments. Aim We aimed at describing the potential clinical cardiotoxicity of oncological treatments in a cohort of consecutive HCM patients, systematically followed up at two national referral centres for HCM. Methods We retrospectively analysed all clinical and instrumental data of all consecutive HCM patients who underwent oncological treatment between January 2000 and December 2020, collected in a centralized database. Results Of 3256 HCM patients, 121 (3.7%) had a reported diagnosis of cancer; 109 (90.1%) patients underwent oncological surgery, 45 (37.2%) chemotherapic treatment, 22 (18.2%) chest radiotherapy. After a median follow up of 5 (2-13) years from oncological diagnosis, 32 of the 121 patients (26.4%) died. The cause of death was mainly attributed to the oncological condition, while 4 (12.5%) patients died of sudden cardiac death without previous chemotherapy or chest radiotherapy. No patient interrupted or reduced the dose of oncological treatment due to cardiac dysfunction. No sustained ventricular tachyarrhythmia was induced by chemotherapy or radiotherapy. Conclusions Cancer treatment is well tolerated in HCM patients. In our oncology series, none died of cardiovascular complications induced by chemotherapy or chest radiotherapy and none required interruption or substantial tapering of treatment due to cardiovascular side effects. Although expert multidisciplinary evaluation is mandatory and regimens must be tailored individually, the diagnosis of HCM per se should not be considered a contraindication to radical cancer treatment.

953 KEY ROLE OF GENETIC ANALYSIS IN A FAMILIAR CASE OF HYPERTROPHIC CARDIAC PHENOTYPE AND VENTRICULAR PREEXCITATION RELATED TO PRKAG2 GENE MUTATION

Abstract A 38-year-old male patient (A2) was referred to our ambulatory for paroxysmal atrial fibrillation in young age and ventricular preexcitation. Echocardiographic evaluation showed left ventricle hypertrophy (localized particularly at inter-ventricular septum (SIV) and normal LV ejection fraction. He also had a positive family history of hypertrophic cardiomyopathy since the latter was already diagnosed with the maternal grandmother (M0), the mother (M1) and the two brothers (A1 and A3). His father was apparently healthy (P1- consanguineous third degree of the mother M1). Specifically, the mother (M1) was suffering from non-obstructive hypertrophic cardiomyopathy, and tachy-brady (paroxysmal atrial flutter, sinus arrest) syndrome requiring pacemaker implantation. The firstborn (A1) was affected by paroxysmal atrial fibrillation, ventricular prexcitation and mild hypertrophy of the interventricular septum (SIV). The third child (A3) had a diagnosis of hypertrophic cardiomyopathy and a history of successfully ablation of a left postero-septal accessory pathway. A3 suffered also by paroxysmal typical atrial common flutter. Genetic analysis of the proband A2 confirmed a heterozygous pathological mutation of the PRKAG2 gene. Thus, genetic analysis was extended to the other two brothers A1 and A3 and the mother. We proposed to the all three brothers electrophysiological study in order to assess arrhythmic substrate and appropriate therapy (strict FUP, PM or ICD implantation). Mutation of the PRKAG2 gene is a rare disease, classified as non-lysosomal cardiac glycogenosis with clinical onset in late adolescence or in the third decade of life and presents an autosomal dominant inheritance with complete penetrance. It is associated with cardiac arrhythmias, such as ventricular preexcitation (Wolff-Parkinson-White syndrome), sinus node disease, atrioventricular block, atrial fibrillation. Genetic analysis has a crucial role especially in the evaluation of inheritance with autosomal dominant transmission and regarding the prognostic impact, since PRKAG2 gene mutation involved a greater arrhythmic risk comparing with other subtypes of hypertrophic cardiomyopathy. Affected patients should be closely monitored to facilitate early detection of arrhythmia and conduction problems. PRKAG2 mutation should be considered in patients with LVH who develop AF or require permanent pacemakers at a young age. Early recognition is important to allow prompt identification and appropriate management of genetic carriers.

185 BETA-BLOCKERS OR CALCIUM CHANNEL BLOCKERS IN HYPERTROPHIC CARDIOMYOPATHY

Abstract Background Guidelines recommend betablockers (BB) as first line therapy in symptomatic patients with hypertrophic cardiomyopathy (HCM). A secondary role in the therapeutic algorithm is assigned to non-dihydropyridine calcium channel blockers (ND-CCB). Since no randomized comparison trials between the two drugs have been made so far, the aim of the present analysis was to evaluate the prognostic impact of BB and ND-CCB in a cohort of patients with HCM, either obstructive or not. Methods From a cohort of 1434 patients with a diagnosis of HCM included in the French register REMY, we retrospectively analysed 601 individuals treated with BB or ND-CCB. Patients taking both BB and ND-CCB or none, patients who already had an implantable cardioverter defibrillator or a pacemaker and who had already undergone a procedure of atrial fibrillation (AF) ablation or of septal reduction therapy were excluded. Results Out of 601 HCM patients, 545 (91%) were treated with BB and 56 (9%) with ND-CCB. At 8-year follow-up no differences were observed as regard the composite endpoint of cardiovascular death, hospitalization for heart failure and hospitalization for AF (133 [24%] vs. 9 [16%] for patients taking BB or ND-CCB respectively, HR 1.84, 95% CI 0.94–3.63). Patients taking ND-CCB were less symptomatic at long-term follow-up but experienced more drug interruptions or changes. Conclusions In a real-world cohort of patients with HCM, ND-CCB therapy was not associated with a higher incidence of adverse events compared to BB therapy.

Diagnosis of hypertrophic cardiomyopathy with microvascular dysfunction by cadmium-zinc-telluride-based myocardial perfusion SPECT:a case report

通过碲锌镉心脏专用单光子发射计算机断层成像术（CZT-SPECT）动态心肌血流定量显像发现一肥厚型心肌病患者左心室整体及冠状动脉分支区域冠状动脉血流储备值均降低，提示该患者冠状动脉微血管生理功能异常，其对准确诊断和评估肥厚型心肌病具有重要的补充价值，同时对此类患者的治疗及预后评估具有重要的参考价值。.

Pharmacokinetics of a single dose of Aficamten (CK-274) on cardiac contractility in a A31P MYBPC3 hypertrophic cardiomyopathy cat model.

Hypertrophic cardiomyopathy (HCM) is the most prevalent cardiac disease in cats and lacks efficacious preclinical pharmacologic intervention, prompting investigation of novel therapies. Genetic mutations encoding sarcomeric proteins are implicated in the development of HCM and small molecule myosin inhibitors are an emerging class of therapeutics designed to target the interaction of actin and myosin to alleviate the detrimental effects of inappropriate contractile protein interactions. The purpose of this study was to characterize the pharmacodynamic effects of a single oral dose of the novel cardiac myosin inhibitor aficamten (CK-274) on cardiac function in purpose bred cats with naturally occurring A31P MYBPC3 mutation and a clinical diagnosis of HCM with left ventricular outflow tract obstruction (LVOTO). Five purpose bred cats were treated with aficamten (2mg/kg) or vehicle and echocardiographic evaluations were performed at 0, 6, 24, and 48 h post-dosing. High dose aficamten (2mg/kg) reduced left ventricular fractional shortening (LVFS%) by increasing the LV systolic internal dimension (LVIDs) and reduced isovolumic relaxation time (IVRT) compared with baseline without significant adverse effects. The marked reduction in systolic function and reduced IVRT coupled with an increased heart rate in treated cats, suggest a lower dose may be optimal. Further studies to determine optimal dosing of aficamten are indicated.

Risk of incident mental disorders in hypertrophic cardiomyopathy: a nationwide propensity-matched study.

We sought to determine the risk of mental disorders in patients with hypertrophic cardiomyopathy (HCM) compared with those without HCM. This is a retrospective propensity score-matched cohort study using nationwide population-based data from the Korean National Health Insurance Service. Overall, 4046 patients with HCM and 12138 matched individuals were followed up until the first diagnosis of mental disorders or the end of the follow up. The primary outcome was a composite of incident mood, anxiety, stress-related, or somatoform disorders. Secondary outcomes included two components of the primary outcome (i.e. mood disorders and anxiety/stress-related/somatoform disorders). During a median follow-up period of 4.1 years, the incidence rate of the primary outcome was 54.4 and 31.5/1000 person-years among the HCM and control groups, respectively, resulting in a hazard ratio (HR) of 1.719 (95% confidence interval: 1.589-1.860). Within the first month after HCM diagnosis, the HR for the primary outcome was 3.074 (2.096-4.508). Beyond 1 month, the HRs decreased, ranging from 2.281 (1.952-2.665) during 1-12 months, to 2.087 (1.831-2.380) during 12-36 months and 1.258 (1.090-1.452) after 36 months of follow up. Similar results were observed for the secondary outcomes. In sensitivity analysis, the risk of the specific categories of mental disorders, including single or recurrent depressive episodes and anxiety disorders, was also higher in patients with HCM than matched controls. HCM was significantly associated with the risk of incident mental disorders, particularly within 1 year after HCM diagnosis, underscoring the importance of screening mental health problems, including mood and anxiety disorders, in patients with HCM.

Abstract 11055: Outcomes and Progression of Rasopathy-Associated Hypertrophic Cardiomyopathy

Background: RASopathy associated hypertrophic cardiomyopathy (HCM) is a frequent cause of pediatric onset HCM. RAS pathway inhibitors are a precision therapeutic option for RASopathy associated HCM. However, limited understanding of HCM progression and correlation with clinical outcomes currently restrict use to a compassionate basis, primarily in infancy. We hypothesize review of RASopathy associated HCM progression and outcomes will demonstrate burden of disease throughout childhood with the goal to identify high risk populations who may benefit from targeted therapies. Methods: A single-center retrospective review identified 59 patients with a diagnosis of HCM and a RASopathy. Echocardiographic, clinical, and molecular data were collected through chart review with echocardiographic measurements at set time points from neonate to young adult. Results: There was high overall mortality in our cohort (20.3%, n = 12). Cardiac arrest, transplant, or death was significantly higher in patients with heart failure in infancy (defined by need for diuretic use) (p<0.001) (Fig 1A). There were no differences by syndrome or genotype. Pulmonary valve (PV) intervention was 16.9% (n = 10) and largely limited to infancy with median age 0.79 years (IQR 0.34-1.63) at first intervention. Incidence of atrial arrhythmias was 13.6% (n = 8) with median age of onset 0.44 years (IQR 0.35-0.88). Rates of septal myectomy were high (23.7%, n = 14). Myectomies, however, were not limited to infancy with median age at first myectomy 3.10 years (IQR 1.09-10.49) (Fig 1B). 21.4% (n = 3) required repeat myectomy. Conclusions: In contrast to previous research, our data suggest there is significant continued HCM growth outside of infancy as evidenced by high incidence of myectomy throughout childhood and young adulthood with frequent need for repeat myectomy. These suggest potential use of targeted therapies outside of infancy with further study needed to identify high-risk populations.

Abstract 14861: Decisional Factors Affecting Genetic Testing Uptake Among Black Adults With Hypertrophic Cardiomyopathy

Introduction: Black adults are underrepresented in hypertrophic cardiomyopathy (HCM) research and experience disparities in HCM - related variant interpretation due to a lack of diversity in genomic reference databases. This is compounded by lower HCM genetic testing utilization among this population. The objective of the qualitative study was to explore decisional factors affecting genetic testing use among a sample of Black adults with HCM. Methods: We used purposive sampling to recruit adults with clinical HCM and had undergone clinical genetic testing for HCM, self-identified as Black/African American, and were receiving care at a large urban academic center. Semi-structured individual interviews were conducted and inductive qualitative content analysis was performed to identify themes related to decisional factors for HCM genetic testing utilization. Quantitative descriptive analysis included demographics and genetic literacy evaluation via the Rapid Estimate of Adult Literacy in Genetics (REAL-G) Results: The sample included 30 individuals (15, 50% women), mean (SD) age 48.8 (17.2) years. Ten (33.3%) individuals had likely-pathogenic/pathogenic variants on clinical genetic testing. REAL-G scores were median (IQR) 62.5 (61;63), signifying a high-school literacy level. Almost half (46.7%) of participants reported finding at least some difficulty paying for basic necessities. The most common themes in decision-making regarding genetic testing utilization included out-of-pocket test costs and a positive relationship with HCM providers, followed by self-care and family concerns. Additional themes emerged concerning individual paths to an HCM diagnosis, including seeing multiple providers and navigating layers of the healthcare system, prior to evaluation by an HCM specialist. Conclusions: This study identified decisional facilitators regarding genetic testing use among a cohort of Black adults with HCM. Future work may focus on identifying barriers and designing interventions to improve genetic testing utilization in this population.

Natural language processing for identification of hypertrophic cardiomyopathy patients from cardiac magnetic resonance reports

BackgroundCardiac magnetic resonance (CMR) imaging is important for diagnosis and risk stratification of hypertrophic cardiomyopathy (HCM) patients. However, collection of information from large numbers of CMR reports by manual review is time-consuming, error-prone and costly. Natural language processing (NLP) is an artificial intelligence method for automated extraction of information from narrative text including text in CMR reports in electronic health records (EHR). Our objective was to assess whether NLP can accurately extract diagnosis of HCM from CMR reports.MethodsAn NLP system with two tiers was developed for information extraction from narrative text in CMR reports; the first tier extracted information regarding HCM diagnosis while the second extracted categorical and numeric concepts for HCM classification. We randomly allocated 200 HCM patients with CMR reports from 2004 to 2018 into training (100 patients with 185 CMR reports) and testing sets (100 patients with 206 reports).ResultsNLP algorithms demonstrated very high performance compared to manual annotation. The algorithm to extract HCM diagnosis had accuracy of 0.99. The accuracy for categorical concepts included HCM morphologic subtype 0.99, systolic anterior motion of the mitral valve 0.96, mitral regurgitation 0.93, left ventricular (LV) obstruction 0.94, location of obstruction 0.92, apical pouch 0.98, LV delayed enhancement 0.93, left atrial enlargement 0.99 and right atrial enlargement 0.98. Accuracy for numeric concepts included maximal LV wall thickness 0.96, LV mass 0.99, LV mass index 0.98, LV ejection fraction 0.98 and right ventricular ejection fraction 0.99.ConclusionsNLP identified and classified HCM from CMR narrative text reports with very high performance.

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.

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

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 = <0.001) (Figure1). During the study period, there was a significant decrease in the prevalence of heart failure (p = <0.001), ischemic heart disease (p = <0.001), and chronic obstructive pulmonary syndrome (p = <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

Characterization of sudden death etiologies in a Portuguese population younger than 40 years-old

Abstract Background The incidence and pathogenesis of sudden death (SD) in the young adult population in Portugal remains to be clarified. Some of the causes are known to be hereditary and a better understanding of these can have implications on the development of a national screening program for relatives of SD victims. Purpose To describe the leading causes of sudden cardiac and non-cardiac death in a young adult Portuguese population (≤40 years-old). Methods The authors retrospectively reviewed cases from a national database regarding individuals who underwent an autopsy, between 2012 and 2016, at 6 districts of mainland Portugal plus the islands. All young adults (1–40 years-old) who had a sudden unexpected death were included and violent deaths were excluded. This study was approved by the Institute Ethics Committee. We reviewed the autopsy files and collected demographic, clinical, necropsic, anatomopathological and toxicological data from each case. We performed statistical analysis using Stata 13.0 software. Results During a 5-year period, out of an estimated total of 2101 deaths in ages 1 to 40, 175 SD were identified. SD victims had a mean age of 32±9 years-old, the majority being of male gender (69%,n=120). There were 115 (66%) cases of SD of confirmed cardiac origin (see Table 1). The remaining causes were respiratory (18%), cerebral (7%), digestive (6%), endocrinologic (2%), urinary (1%), infectious (1%). The most frequent cardiac cause being coronary atherosclerosis (n=40,35%), which included lesions with estimated luminal narrowing >75% and/or documented type 1 acute myocardial infarction. These patients were older (31±8 vs 35±4, p<0.020), had a minimum age of 26 years, and more frequently male (85% vs 61%, p=0.011). There were 17 (15%) victims who had cardiopathy with histopathological hypertrophy (5 of them with associated fibrosis), and the diagnosis of hypertrophic cardiomyopathy (HCM) was possible in only 3 (3%) victims. In addition, there were 15 (13%) who died from pulmonary embolism who were predominantly women (23% vs 80%, p<0.001). There were 8 (7%) victims with a final diagnosis of cardiopathy with histopathological dilation, 2 possibly corresponding to post-partum cardiomyopathy (CMP), 1 to ethanolic CMP and 1 to ventricular dilation and fibrosis due to previous myocarditis, who had associated hepatitis with signs of activity. Six cases of acute myocarditis were identified, who were significantly younger, comparing to patients dying from other cardiac causes (23±13 vs 33±7, p=0,011). There were 2 cases of HCM with genetic data, one of which was complemented during molecular autopsy. Conclusions During a 5-year period, the cumulative incidence of SD in a region of Portugal is very low (n=175), cardiac causes being present in 66% of the cases. The most frequent cardiac cause is coronary atherosclerosis (35%). Funding Acknowledgement Type of funding sources: None.

Narrowing Beta-myosin hot spots in its association with hypertrophic cardiomyopathy

Abstract Introduction MYH7 encodes to β-cardiac myosin heavy chain, a large and pleomorphic protein, conformed by different and well-functionally characterized domains. This gene has an enormous contribution to hypertrophic cardiomyopathy (HCM) but also to other cardiomyopathies such as dilated, non-compaction and restrictive cardiomyopathy (and overlapping phenotypes). There are specific and adapted recommendations for classifying variants in this gene regarding its association with HCM; one of the aspects was the location of variants in the head domain, encompassing 181–937 residues as moderate ACMG criteria (Kelli et al., 2018). Objectives The purpose of this analysis was to determine if more specific regions of MYH7are enriched in HCM cases. This analysis could help to better characterise those regions where identifying a novel missense variant could reinforce their pathogenicity. Methods We included in the analysis 26,929 consecutives unrelated probands in which MYH7 was sequenced by NGS, referred from different countries and centres. We performed an enrichment analysis comparing the prevalence of rare missense variants (pre-established MAF cut-off 0.004%) in cases with the diagnosis of HCM versus their frequency in non-cardiomyopathy cases (internal controls, OR_int, comprising aortic diseases, channelopathies and dyslipidaemias) and in gnomAD population (external controls, OR_ext). Comparison between groups was performed using the Student's t-test; p value <0.05 was considered to indicate statistical significance. The rationale of this grouping was to avoid skewed analysis, given the high degree of overlapping cardiomyopathies observed in this gene. Results HCM was the diagnosis in 10,064 cases. 8,975 probands with a non-cardiomyopathy phenotype were used as internal controls; 7,890 cases with other MYH7-related phenotypes (restrictive, dilated, non-compaction and skeletal myopathies) were not included in the analysis. Rare missense variants in MYH7 were enriched in HCM cases (OR_int = 11.15; OR_ext =12.44) and in the pre-established hot spot head domain (OR_int = 16.43; OR_ext = 24.53). However, the regions with the highest odds ratios in both external and internal comparison were the central converter domain (residues 711–755, OR_int = 44.39; OR_ext = 50.27) and actin-binding region (residues 647–664, OR_int =18.77; OR_ext = 69.32). Conversely, the tail region (both S2 subfragment and light meromyosin region, LMM), had the lowest OR in this analysis. Conclusions Previously reported hotspot (head) is significantly enriched in HCM cases, but some specific regions within this domain, such as central converter and acting-binding region, could have a relatively higher contribution. These results reinforce the current approach, but on the other hand, show an asymmetric contribution within the head domain. This fact may have an impact on the reassessment of the variant classification in this gene towards a more precise approach. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Health in Code

Exercise unmasks impaired vascular and cardiac hemodynamic in patients with hypertrophic cardiomyopathy

Abstract Background/Introduction Exertional dyspnea is a common finding in patients with Hypertrophic Cardiomyopathy (HCM), yet little data is available regarding the hemodynamic disturbances that lead to symptom development in this population. Purpose To investigate the mechanisms involved in the functional limitation of patients with HCM. Methods We prospectively studied 20 symptomatic patients with confirmed diagnosis of HCM. Assessment included NT-pro BNP levels, echocardiogram, and invasive characterization, where subjects also underwent invasive cardiopulmonary exercise testing. Results Median patient age was 57 (48–66) years old and 15 (75%) were male. Basal NT-pro BNP was elevated (748 pg/mL [406–1082]) and 8 (40%) subjects had NYHA functional Class III despite optimal medical treatment. Sarcomeric abnormal mutations were identified in 12 subjects (60%), most frequently in MYBPC3. Ultrasound imaging showed marked left ventricle (LV) hypertrophy (LV Mass Index 140 g/m2 [109–161]), with signs of LV outflow obstruction in 13 (65%) subjects. All patients displayed preserved ejection fraction (68% [61–73]). Significant mitral regurgitation was present in 5 subjects and median E/e' was 9.87 [6.43–13.14]. At rest, biventricular filling pressures were relatively normal, with upper limit mean Pulmonary Pressure (Table). Patients exercised for 6.4 (95% CI: 5.6–7.2) min, achieving a respiratory exchange ratio of 1.11 (1.02–1.17). All subjects displayed normal cardiac output at rest (5.6 L/min (3.7–7.5)), that increased during exertion, due mostly to a rise in heart rate (p<0.0001). Exercise doubled LV End-Diastolic Pressure from 15.3 (11.5–19.1) mmHg at baseline to 30.4 (26.6–34.3) mmHg at peak VO2 (p<0.0001), whereas mean pulmonary pressure increased from 21 (14–29) mmHg to 40 (33–47) mmHg (p<0.0001). Remarkably, although arterial hemodynamics were relatively normal at baseline, exercise induced significant increases both in the continuous (systemic vascular resistance) and pulsatile components of vascular load (Impedances, p<0.05; Table 1) (Figure 1). This increase in afterload during exertion has not been previously documented in HCM. The decreased compliance derived, can also play a role in the elevated filling pressures documented on exertion. Conclusion Exercise unmasks adverse hemodynamics in HCM, severely increasing LV filling pressures and showing systemic arterial dysfunction. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III, Spain.

The impact of adrenoceptor-1 gene polymorphism on structural and functional features in patients with hypertrophic cardiomyopathy

Abstract Background The adrenergic system plays a central role during the clinical course of hypertrophic cardiomyopathy (HCM) and hence beta-blocker therapy is the first-line treatment option according to current guidelines. Previous studies demonstrated variable cellular response to an adrenergic stimulus due to adrenoceptor-1 (ADRB-1) gene polymorphism in several patient groups including hypertension and dilated cardiomyopathy. Moreover, the impact of beta-blockers is also variable in these patients. Purpose We aimed to investigate the impact of ADRB-1 gene polymorphism on structural and functional features among patients with HCM. Methods In this study, we investigated the roles of Arginin389Glycine and Glycine49Serine polymorphism. Patients with a clear diagnosis of HCM according to current guidelines were included. Structural features including maximal wall thickness, interstitial fibrosis and left ventricular/atrial volumes were obtained using cardiac MRI and transthoracic echocardiography. Functional features including heart rate, blood pressure, left ventricular outflow obstruction were also recorded. The risk of sudden cardiac death was calculated using the HCM risk score. The impact of beta-blocker therapy on heart rate and blood pressure were also compared. Results After the exclusion of patients, 147 patients were included in the study. 77% of the study population were male and the mean age was 49.5 years. The hypertrophic segment was septum in 83% of the study population. The mean maximum wall thickness was 20 mm (19–23). With respect to Ser49Gly polymorphism, Serine homozygotes demonstrated higher late-gadolinium enhancement and indicator of interstitial fibrosis (p: 0.007). In concordance with higher LGE, the presence of fragmented QRS on surface ECG (p: 0.026) and a higher prevalence of non-sustained ventricular tachycardia (p: 0.016) in these patients were observed. The risk of sudden cardiac death was also higher in Ser49 homozygotes (p: 0.041). However, with respect to Arg389Gly gene polymorphism, there was no significant difference between Arg389 homozygotes, Arg389Gly heterozygotes and Gly389 homozygotes in terms of structural and functional features. The vast majority of patients reported improved functional capacity and decreased shortness of breath during the follow-up regardless of ADRB-1 gene polymorphism which is objectively validated by decreased pro-BNP levels in all patients. Conclusion Our results indicated that ADRB-1 gene polymorphism, particularly Ser49Gly gene polymorphism may have a significant role during the clinical course of HCM. Since Ser49 homozygote patients demonstrated higher interstitial fibrosis and a higher risk of sudden cardiac death, further studies are required to determine the significance of Ser49Gly gene polymorphism in HCM patients. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Bilimsel Arastırma Projesi (BAP) - Istanbul University - Cerrahpasa, Cerrahpasa Medical School

Mitral valve abnormalities in decedents of sudden cardiac death due to hypertrophic cardiomyopathy and idiopathic left ventricular hypertrophy.

Mitral valve abnormalities in decedents of sudden cardiac death due to hypertrophic cardiomyopathy and idiopathic left ventricular hypertrophy.

RELATIONSHIPS BETWEEN LEFT VENTRICULAR MASS AND QRS DURATION IN HYPERTROPHIC CARDIOMYOPATHY AND HYPERTENSIVE HEART DISEASE: A NEW DIAGNOSIS TOOL

RELATIONSHIPS BETWEEN LEFT VENTRICULAR MASS AND QRS DURATION IN HYPERTROPHIC CARDIOMYOPATHY AND HYPERTENSIVE HEART DISEASE: A NEW DIAGNOSIS TOOL

247.7: Trends and Risk Factors for Mortality While Awaiting Heart Transplantation: A UNOS Registry Analysis

Background: Orthotopic heart transplantation (OHT) remains the gold standard treatment of end-stage heart failure. In order to address organ scarcity, allocation systems aim to decrease waitlist mortality while maintaining acceptable post-transplant outcomes. The purpose of this study was to examine the characteristics of patients who suffered mortality on the waitlist versus those who underwent transplantation, as well as the impact of recent changes in the United States heart allocation policies on these outcomes. Methods: The United Network for Organ Sharing database was queried, and adult, isolated OHT candidates listed for transplant within the United States from 11/5/2015 to 9/30/2021 were analyzed. Baseline characteristics among candidates that either were transplanted, or had been removed from the waitlist due to death clinical deterioration were compared. Comparisons were also made between heart allocation policy (pre or post-10/18/2018) time eras. Multivariable competing risk regression was conducted to identify risk-adjusted predictors of transplantation from the waitlist. Additionally, predictors of the outcome of death or de-listing from the waitlist due to clinical decline were also modeled. Results: During the study period, a total of 13,575 recipients were transplanted (6,926 under the old policy and 6,649 under the new). A total of 1,875 candidates died or were de-listed (1,235 listed under the old policy and 640 listed under the new). In a comparison of baseline characteristics at time of listing, candidates that were transplanted differed significantly to those who were de-listed due to death or clinical decline with respect to age, heart failure etiology, mechanical circulatory support bridging, and baseline comorbidity (Table). In a multivariable model, waitlisting under the new allocation policy was associated with reduced hazards for death or de-listing (HR 0.57, 95% CI 0.51-0.63; P<0.001), and increased hazards for undergoing transplantation (HR 1.36; 95% CI 1.31-1.41; P<0.001). The two largest predictors of transplantation were bridging with an intra-aortic balloon pump (HR 2.13, 95% CI 1.97-2.31; P<0.001) and AB blood type (HR 1.43, 95% CI 1.30-1.57; P<0.001). The strongest predictors of death or de-listing were diagnosis of hypertrophic cardiomyopathy (HR 3.77, 95% CI 2.69-5.29; P<0.001) or biventricular hemodynamic support in the form of either extracorporeal membrane oxygenation (HR 2.59, 95% CI 1.96-3.42; P<0.001), total artificial heart (HR 2.36, 95% CI 1.28-4.35; P=0.006), or combined right and left ventricular assist device support (HR 2.45, 95% CI 1.71-3.50; P<0.001). Conclusions: Since the United States 2018 heart allocation policy change, waitlisted candidates are more likely to be transplanted and less likely be de-listed due to death or clinical decline. Need for biventricular mechanical circulatory support at time of waitlisting are associated with higher risk of death or falling too ill for transplantation.

HYPERTROPHIC CARDIOMYOPATHY SIMULATING AN ACUTE CORONARY SYNDROME

Hypertrophic cardiomyopathy corresponds to myocardial hypertrophy &gt;15mm or &gt;13mm in case of familial hypertrophic cardiomyopathy (HCM).We report the case of a 31-year-old patient with no cardiovascular risk factors and no notable history who was admitted to the emergency room for the management of prolonged resting chest pain associated with electrical changes in the electrocardiogram (EKG)given the clinical symptomatology and the overshift with the mirror image. A coronary angiography was performed and came back without any particularity. The diagnosis of non-obstructive septal HCM was made based on echocardiography and cardiac magnetic resonance imaging (MRI) findings.The patient stayed in the cardiac intensive care unit with a good clinical course, he was declared to be discharged under symptomatic treatment given the non-obstructive nature and the low risk of sudden death.