Case Of Hypertrophic Cardiomyopathy Research Articles

A case of hypertrophic cardiomyopathy with previous aortic valve replacement

We describe a 45-year-old patient who was diagnosed with hypertrophic obstructive cardiomyopathy (HOCM) after the aortic valve replacement surgery. Enlarged left atria, thickened ventricular septum, left ventricular outflow tract stenosis, moderate mitral regurgitation and mild tricuspid regurgitation in the echocardiography were found. We offered the patient the new minimally invasive treatment modality: percutaneous intra-myocardial septal radiofrequency ablation (PIMSRA). We demonstrate the safety and efficacy with pictures. One month after surgery, the patient recovered well with improved symptoms of chest tightness, and no LVOT obstruction or arrhythmia.

Case of Hypertrophic Cardiomyopathy with Clinical Progression to Restrictive Physiology

Abstract Hypertrophic cardiomyopathy (HCM) is defined as an unexplained left ventricular (LV) hypertrophy ≥15 mm (13 mm if family history present) occurring in the absence of identifiable factor that may account for LV wall thickening, including pressure overload and infiltrative or storage disorder. Restrictive physiology is a pattern of ventricular filling with increased myocardial stiffness leading to elevation of ventricular pressure, causing diastolic dysfunction. A 60-year-old man was brought to the hospital with progressive worsening breathlessness for 2 days and bilateral lower limb swelling. The patient was a known case of HCM, ischemic heart disease (IHD) with single-vessel disease – ostial D1 70% stenosis, atrial fibrillation (AF), status post radiofrequency ablation, moderate LV systolic dysfunction (ejection fraction [EF] – 30%), with recurrent admission due to heart failure. The patient presented with hypotension and bilateral lower limb swelling, and systemic examination showed bilateral crepitations. The patient was diagnosed with acute decompensated heart failure, heart failure with reduced EF, HCM, old IHD, and AF with controlled ventricular rate. Serial two-dimensional echocardiography showed the progression of HCM to restrictive physiology. The patient deteriorated and was planned for a heart transplant with bridging LV assist device therapy. The transition is not usually reported, and literature related to this is scarce; hence, this case is being reported.

Re-evaluating the Incidence and Prevalence of Clinical Hypertrophic Cardiomyopathy: An Epidemiological Study of Olmsted County, Minnesota

ObjectiveTo contemporaneously reappraise the incidence-rate, prevalence, and natural history of hypertrophic cardiomyopathy (HCM) in Olmsted County, Minnesota, from 1984 to 2015. Patients and MethodsA validated medical-record linkage system collecting information for residents of Olmsted County was used to identify all cases of HCM between January 1, 1984, and December 31, 2015. After adjudication of records from Mayo Clinic and Olmsted Medical Center, data relating to diagnoses and outcomes were abstracted. The calculated incidence rate and prevalence were standardized to the US 1980 White population (age- and sex-adjusted) and compared with a prior study examining the years 1975-1984. ResultsTwo hundred seventy subjects with HCM were identified. The age- and sex-adjusted incidence rate was 6.6 per 100,000 person-years, and the point prevalence of HCM on January 1, 2016, was 89 per 100,000 population. The incidence rate and point prevalence of HCM on January 1, 2016, standardized to the US 1980 White population (age- and sex-adjusted), were 6.7 (95% CI, 7.1 to 8.8) per 100,000 person-years and 81.5 per 100,000 population, respectively. The incidence rate of HCM increased each decade since the index study. Individuals with HCM had a higher overall standardized mortality rate than the general population with an observed to expected HR of 1.44 (95% CI, 1.21 to 1.71; P<.001) which improved by each decade. ConclusionThe incidence and prevalence of HCM are higher than rates reported from a prior study in the same community examining the years 1975-1984, but lower than other study cohorts. The risk of mortality in HCM remains higher than expected, albeit with improvement in rates of mortality observed each decade during the study period.

Gene-Specific Discriminative Echocardiogram Findings in Hypertrophic Cardiomyopathy Determined Using Artificial Intelligence: A Pilot Study

Hypertrophic cardiomyopathy (HCM) is among the most common forms of cardiomyopathies, with a prevalence of 1:200 to 1:500 people. HCM is caused by variants in genes encoding cardiac sarcomeric proteins, of which a majority reside in MYH7, MYBPC3, and TNNT2. Up to 40% of the HCM cases do not have any known HCM variant. Genotype–phenotype associations in HCM remain incompletely understood. This study involved two visits of 46 adult patients with a confirmed diagnosis of HCM. In total, 174 genes were analyzed on the Next-Generation Sequencing platform, and transthoracic echocardiography was performed. Gene-specific discriminative echocardiogram findings were identified using the computer vision library Fast AI. This was accomplished with the generation of deep learning models for the classification of ultrasonic images based on the underlying genotype and a later analysis of the most decisive image regions. Gene-specific echocardiogram findings were identified: for variants in the MYH7 gene (vs. variant not detected), the most discriminative structures were the septum, left ventricular outflow tract (LVOT) segment, anterior wall, apex, right ventricle, and mitral apparatus; for variants in MYBPC3 gene (vs. variant not detected) these were the septum, left ventricle, and left ventricle/chamber; while for variants in the TNNT2 gene (vs. variant not detected), the most discriminative structures were the septum and right ventricle.

Abstract 16623: Extra-Cellular Volume Fraction Analysis on Cardiac CT is Useful for Predicting the Prognosis of Hypertrophic Cardiomyopathy

Introduction: Extra-Cellular volume fraction (ECV) analysis on MRI helps predict ventricular arrhythmia in hypertrophic cardiomyopathy (HCM). But the performance of cardiac MRI takes time, and there are also several contraindications. Cardiac CT is more versatile than cardiac MRI and is also helpful in screening coronary artery disease. We investigated the usefulness of ECV analysis on CT for the prognosis of HCM.Aim: To determine the utility of ECV analysis on CT to predict the prognosis in patients with HCM. Methods: Eighty-five HCM patients who underwent cardiac CT from December 2008 to March 2022 were analyzed. Left ventricular (LV) ECV (LV-ECV) on CT was measured, and we investigated the relationship between LV-ECV on CT and the major adverse cardiac events (MACEs) (cardiac death, fatal arrhythmia, and heart failure hospitalization) after CT. Results: All patients were followed for 69 ± 58 months after cardiac CT and 14 patients (16%) had MACEs. They had a significantly higher LV-ECV and lower ejection fraction (LVEF) than those without MACEs(42.4 ± 8.4% vs. 34.0 ± 7.0%, P=0.003, and (56.7 ± 11.8% vs. 66.7 ± 7.0%, P=0.011). The percentage of dilated phase HCM was significantly higher in the patients with MACEs than those without MACEs (21% vs 0%, p=0.003). LV-ECV was the only significant predictor of MACEs based on the multivariate analysis by Cox proportional hazard model (hazard ratio 1.13, 95% confidence interval 1.06-1.21). The optimal threshold of LV-ECV to predict MACEs was 37.59% based on the receiver operating characteristic analysis. The sensitivity and specificity of LV-ECV to predict MACEs were 79% and 75% at the best cut-off, and the area under the curve was 0.78 (Figure A). The patients with LV-ECV ≥ 37.59% (29 patients) had significantly higher MACEs than those with LV-ECV &lt; 37.59% during the follow-up periods (P &lt;0.001) (Figure B). Conclusion: ECV analysis on CT helped predict MACEs in HCM cases.

Abstract 18022: Multiplexed Generation and Functional Annotation of Hypertrophic Cardiomyopathy-Associated MYH7 Missense Variants in Isogenic Gene-Edited Stem Cell-Derived Cardiomyocytes

Hypertrophic cardiomyopathy (HCM) is an inheritable cardiac condition affecting 1:200-500 people and is characterized by left ventricular hypertrophy that can cause heart failure. Autosomal-dominant, missense mutations in MYH7 (encoding MHC-β) cause 33% of genotype + HCM cases. Despite this, 75% of MYH7 missense variants are of unknown clinical significance (VUS). Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can elucidate the effect(s) of VUS, however, new variant identification by genetic testing outpaces methods to gene edit hiPSCs. Thus, we developed a method called CR ISPR a On- T arget E diting R etrieval (CRaTER) which increased successful gene-editing 25-fold over current methods. We leveraged CRaTER to enrich for edited hiPSCs, generating a library of 113 MYH7 missense variants. As mutations can reduce protein stability and abundance, we flow sorted MYH7 variant hiPSC-CMs into bins based on differing MHC-β protein abundance followed by next generation sequencing to calculate variant abundance scores. This multiplexed assay identified 31 residue substitutions as functionally abnormal, including all tested pathogenic variants and VUS. MHC-β depletion was validated in clonal hiPSC-CMs and by Western blotting of patient myocardium with a MYH7 mutation. Additionally, we found that severe MHC-β depletion is associated with increased cell size, a hallmark pathological phenotype of HCM. Finally, single-cell contractility analyses of hiPSC-CMs with a pathogenic MYH7 variant revealed hyperdynamic physiology relative to isogenic controls, suggesting an association between MHC-β loss and systolic dysfunction. Together, CRaTER enables the generation of isogenic hiPSC variant libraries at unprecedented scale for differentiation to disease-relevant cell types. Functional analyses of MYH7 variant hiPSC-CMs have revealed a novel correlation between MHC-β protein depletion and pathogenicity that accurately predicts MYH7 variant effect and has implications for future MYH7 variant effect interpretations.

Abstract 16540: Left Ventricular Longitudinal Strain Analysis Using Four-Dimensional Computed Tomography for the Detection of Apical Sparing in Cardiac Amyloidosis

Introduction: Cardiac computed tomography (CT) not only allows for coronary artery evaluation but also enables myocardial assessment, including left ventricular (LV) ejection fraction (LVEF) and extracellular volume fraction. Advanced software makes it possible to analyze LV longitudinal strain (LS) on CT (Figures A and B). Hypothesis: LS analysis using four-dimensional cardiac CT is helpful for the differential diagnosis of LV hypertrophied myocardial diseases and detect cardiac amyloidosis (CA). Methods: We analyzed 45 patients with LV hypertrophied myocardial diseases who underwent cardiac CT using 256-detector row or 320-detector row CT in our institutions since 2009. Fifteen patients of them were diagnosed with CA (69 ± 9 years, 12 males), the other 15 patients were diagnosed with hypertrophic cardiomyopathy (HCM) (63 ± 16 years, nine males), and the rest of the 15 patients were diagnosed with aortic valve stenosis (AS) (83 ± 8 years, seven males). We analyzed LV global LS (GLS) and segmental LS using specific software and four-dimensional CT data. We evaluated relative apical LS as the value dividing the average LS of apical segments by the sum of the average LS of basal segments and mid-ventricular segments (Figure C). If the value was ≥ 1, apical sparing was defined as present. We compared the LS data and the percentage of apical sparing among those three myocardial diseases. Results: There was no significant difference in LVEF among the three groups (54 ± 12%, 58 ± 13%, and 50 ± 18%, respectively; P = 0.39). There was no significant difference in LV global LS among the three groups (-12.2 ± 3.2%, -11.2 ± 5.0%, and -11.0 ± 5.4%, respectively; P = 0.75). Apical sparing was observed in 6 cases (40%) of CA, which was significantly higher than in one case (7%) of HCM or AS (P = 0.02). Conclusions: Advanced image analysis software has made LVLS analysis by cardiac CT possible. It is considered helpful in detecting apical sparing, specifically in CA.

Abstract 17085: An Unusual Case of Severe Hypertrophic Cardiomyopathy in a 23-Year-Old Systemic Lupus Erythematosus Patient on Hydroxychloroquine

A 23-year-old female with Systemic lupus erythematosus (SLE), lupus nephritis, antiphospholipid syndrome, venous thromboembolism, stroke, Libman-Sacks endocarditis, and hypertension presented with right upper and lower extremity weakness, right facial droop, and aphasia. Her home medications included hydroxychloroquine, mycophenolate, apixaban, and losartan. ECG showed normal sinus rhythm, left atrial enlargement, ST and T wave abnormalities in V5 and V6. Computed tomography angiography of the brain showed left middle cerebral artery occlusion. Transthoracic echocardiogram (TTE) showed left ventricular ejection fraction of 65%, severe left ventricular hypertrophy, moderate pericardial effusion, and moderately thickened mitral valve (MV) leaflets. Transesophageal echocardiogram showed large vegetations on atrial aspect of both MV leaflets concerning for Libman-Sacks endocarditis. We attempt to investigate the cause of this hypertrophic cardiomyopathy (HCM) in a young patient with SLE. Few reported cases of HCM in patients with SLE were medication induced. Tacrolimus has been observed to induced HCM in a Japanese patient with dermatomyositis. Hydroxychloroquine has been associated with myocardial thickening. Its use can lead to enlarged myocardiocytes with intracytoplasmic vacuoles consisting of concentric lamellar myelin figures in single membrane bound vesicles, curvilinear bodies, glycogen accumulation and fused mitochondria. Hydroxychloroquine use led to reversible inhibition of lysosomal enzyme activity. Cessation of medication use in both cases led to reduction in left ventricle thickness. These patients, like our own, has no family history of aortic valve stenosis, mitral valve prolapse, or HCM. However, this patient’s use of hydroxychloroquine to treat her SLE can be assumed to be a contributing factor to her HCM. This could suggest possible screening with ECG and TTE in patients taking hydroxychloroquine.

Analysis and evaluation of patient-specific three-dimensional printing in complex septal myectomy.

This study aimed to assess the effectiveness of three-dimensional printing (3DP) in patients with complex hypertrophic cardiomyopathy requiring combined transaortic and transapical septal myectomy. We created 3DP models for 7 patients undergoing this surgery approach between June and October 2022 using silicone-like resin and conducted mock operations. The models were compared with echocardiography to identify abnormal muscle bundles and heart structures. These patients were then compared with a 1:2 matched group without 3DP, considering age, sex and additional operations. The models mostly presenting with midventricular obstruction showed high consistency with original computed tomography data (r = 0.978, P < 0.001). 3DP identified more abnormal muscle bundles than echocardiography, primarily between the interventricular septum and apex. Excised specimens in mock operations mirrored those in actual myectomies. While cardiopulmonary bypass time was not significantly different, a near-20-min decrease was observed in the 3DP group (135.5 ± 31.1 vs 154.4 ± 36.6 min, P = 0.054). While no significant differences in surgical outcomes were observed, 3DP appeared to enhance the visualization and understanding of spatial structures (average Likert scale score 4.0), potentially contributing to surgical proficiency (overall rating score 3.9). The use of 3DP may offer additional value in the preparation and execution of operations for complex hypertrophic cardiomyopathy cases.

The predictive value of cardiac MRI strain parameters in hypertrophic cardiomyopathy patients with preserved left ventricular ejection fraction and a low fibrosis burden: a retrospective cohort study.

Prompt interventions prevent adverse events (AE) in hypertrophic cardiomyopathy (HCM). We evaluated the pattern and the predictive role of feature tracking (FT)-cardiac magnetic resonance (CMR) imaging parameters in an HCM population with a normal left ventricular ejection fraction (LVEF) and a low fibrosis burden. The CMR and clinical data of 170 patients, consisting of 142 HCM (45 ± 15.7 years, 62.7% male) and 28 healthy (42.2 ± 11.26 years, 50% male) subjects, who were enrolled from 2015 to 2020, were evaluated. HCM patients had a normal LVEF with a late gadolinium enhancement (LGE) percentage below 15%. Between-group differences were described, and the potent predictors of AE were determined. A P-value below 0.05 was considered significant. LV global longitudinal, circumferential, and radial strains (GLS, GCS, and GRS, respectively) and the LV myocardial mass index (MMI) were different between the healthy and HCM cases (all Ps < 0.05). Strains were significantly impaired in the HCM patients with a normal MMI. A progressive decrease in LVGLS and a distinct fall in LVGCS were noted with a rise in MMI. AE were predicted by LVGLS, LVGCS, and the LGE percentage, and LVGCS was the single robust predictor (HR, 1.144; 95% CI, 1.080-1.212; P = 0.001). An LVGCS below 16.2% predicted AE with 77% specificity and 58% sensitivity. LV strains were impaired in HCM patients with a normal EF and a low fibrosis burden, even in the presence of a normal MMI. CMR parameters, especially FT-CMR values, predicted AE in our HCM patients.

Temporal trends of hypertrophic cardiomyopathy in Denmark: a nationwide retrospective cohort study

ObjectivesTo describe the population of patients diagnosed with hypertrophic cardiomyopathy (HCM) in Denmark and determine temporal trends in incidence and patient characteristics over time.DesignNationwide retrospective cohort study.SettingDanish nationwide administrative and...

Postmortem Next-Generation Sequencing in an Autopsy Case with Hypertrophic Cardiomyopathy

Postmor tem next-generation sequencing (NGS) plays a crucial role in uncovering previously unidentified genetic causes of death. It provides essential findings useful for counseling affected family members and advancing our understanding of genetic diseases. In this report, we present the first documented autopsy case of hypertrophic cardiomyopathy (HCM) in South Korea in which postmortem NGS was used to identify a novel mutation. A 40-year-old male with no relevant medical history experienced sudden death at home. The autopsy revealed cardiac findings consistent with HCM but no other potential causes of sudden death. Through postmortem NGS analysis, a novel pathogenic mutation, c.2833_2834del, in MYBPC3 gene, was discovered; hence, this serves as the first report of this mutation in a Korean population. This finding not only confirms the diagnosis of HCM but also provides a plausible explanation for the sudden death. Given the hereditary nature of HCM, genetic counseling is strongly recommended, especially for the deceased’s nine-year-old son, who has a 50% risk of inheriting the mutation. This case underscores the critical role of postmortem NGS in the field of forensic medicine. The significance of NGS and necessity for integration into autopsy investigations are highlighted.

Abstract P1019: High-throughput Generation And Functional Characterization Of Myosin Heavy Chain 7 Variants In Genome-edited Cardiomyocytes

Hypertrophic cardiomyopathy (HCM), an inheritable cardiac condition characterized by idiopathic left ventricular hypertrophy, can cause sudden cardiac death or heart failure. Autosomal-dominant missense mutations in MYH7 (encoding the sarcomeric βMHC protein) account for 33% of genotype-positive HCM cases. While pathogenic MYH7 variants are clinically-actionable, 75% of MYH7 missense variants in ClinVar are variants of unknown significance (VUS). Gene-editing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can help determine the function of MYH7 VUS, however, the discovery of new variants by genetic testing outpaces the ability to gene-edit hiPSCs. Thus, we developed a novel method called CR ISPR a On- T arget E diting R etrieval (CRaTER) which increases the success of gene-editing by 25-fold compared to current methods. We leveraged CRaTER to enrich for hiPSCs edited with a library of MYH7 missense variants and recovered 113 different heterozygous variants. As deleterious mutations can reduce protein stability, we flow sorted MYH7 variant hiPSC-CMs into bins based on differing βMHC abundance followed by next generation sequencing of each bin to calculate variant abundance scores. This assay identified 31 MYH7 missense variants as functionally abnormal (lower abundance scores than synonymous controls), including all known pathogenic variants in the library. This βMHC depletion phenotype was validated in clonal hiPSC-CMs and supported by western blotting of myocardium from a patient with a pathogenic MYH7 missense mutation. Furthermore, we rescued βMHC protein levels by genetically ablating the gene encoding for Muscle RING-finger protein-1, an E3 protein ligase that targets βMHC for degradation, and found that the cardiomyocyte hypertrophy induced by the pathogenic MYH7 E848G HCM variant was significantly blunted. In summary, CRaTER enables the generation of gene-edited hiPSC lines at unprecedented scale. Functional analysis of MYH7 variant hiPSC-CMs reveals a novel correlation between loss of βMHC protein and clinical pathogenicity that can be leveraged for clinical variant interpretation. Interventions that prevent the loss of βMHC may potentially be therapeutic for MYH7 -associated HCM.

Rare Case of Coronary Anomaly, Overview of Hypertrophic Cardiomyopathy with A Different Presentation

Abstract; Coronary artery anomalies are uncommon cardiac diseases. It is mostly detected incidentally in the adult population as well as being usually asymptomatic. Although its prevalence is low, its association with atherosclerosis, arrhythmias, and hypertrophic cardiomyopathy is important for sudden cardiac death. According to the literature, the association of hypertrophic cardiomyopathy with the coronary anomaly is rare. No case of hypertrophic cardiomyopathy accompanied by the absence of the left anterior descending artery has been reported. Therefore our case is special and valuable.

A novel αB-crystallin R123W variant drives hypertrophic cardiomyopathy by promoting maladaptive calcium-dependent signal transduction.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray and cardiac fibrosis, HCM is a highly complex disease with heterogenous clinical presentation, onset and complication. While mutations in sarcomere genes can account for a substantial proportion of familial cases of HCM, 40%-50% of HCM patients do not carry such sarcomere variants and the causal mutations for their diseases remain elusive. Recently, we identified a novel variant of the alpha-crystallin B chain (CRYABR123W) in a pair of monozygotic twins who developed concordant HCM phenotypes that manifested over a nearly identical time course. Yet, how CRYABR123W promotes the HCM phenotype remains unclear. Here, we generated mice carrying the CryabR123W knock-in allele and demonstrated that hearts from these animals exhibit increased maximal elastance at young age but reduced diastolic function with aging. Upon transverse aortic constriction, mice carrying the CryabR123W allele developed pathogenic left ventricular hypertrophy with substantial cardiac fibrosis and progressively decreased ejection fraction. Crossing of mice with a Mybpc3 frame-shift model of HCM did not potentiate pathological hypertrophy in compound heterozygotes, indicating that the pathological mechanisms in the CryabR123W model are independent of the sarcomere. In contrast to another well-characterized CRYAB variant (R120G) which induced Desmin aggregation, no evidence of protein aggregation was observed in hearts expressing CRYABR123W despite its potent effect on driving cellular hypertrophy. Mechanistically, we uncovered an unexpected protein-protein interaction between CRYAB and calcineurin. Whereas CRYAB suppresses maladaptive calcium signaling in response to pressure-overload, the R123W mutation abolished this effect and instead drove pathologic NFAT activation. Thus, our data establish the CryabR123W allele as a novel genetic model of HCM and unveiled additional sarcomere-independent mechanisms of cardiac pathological hypertrophy.

An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiomyopathy that follows an autosomal dominant inheritance pattern. The majority of HCM cases can be attributed to mutation of the MYBPC3 gene, which encodes cMyBP-C, a crucial structural protein of the cardiac muscle. The manifestation of HCM's morphological, histological, and clinical symptoms is subject to the complex interplay of various determinants, including genetic mutation and environmental factors. Approximately half of MYBPC3 mutations give rise to truncated protein products, while the remaining mutations cause insertion/deletion, frameshift, or missense mutations of single amino acids. In addition, the onset of HCM may be attributed to disturbances in the protein and transcript quality control systems, namely, the ubiquitin-proteasome system and nonsense-mediated RNA dysfunctions. The aforementioned genetic modifications, which appear to be associated with unfavorable lifelong outcomes and are largely influenced by the type of mutation, exhibit a unique array of clinical manifestations ranging from asymptomatic to arrhythmic syncope and even sudden cardiac death. Although the current understanding of the MYBPC3 mutation does not comprehensively explain the varied phenotypic manifestations witnessed in patients with HCM, patients with pathogenic MYBPC3 mutations can exhibit an array of clinical manifestations ranging from asymptomatic to advanced heart failure and sudden cardiac death, leading to a higher rate of adverse clinical outcomes. This review focuses on MYBPC3 mutation and its characteristics as a prognostic determinant for disease onset and related clinical consequences in HCM.

Sarcomeric versus Non-Sarcomeric HCM

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disorder and is characterized by left ventricular hypertrophy (LVH), which is unexplained by abnormal loading conditions. HCM is inherited as an autosomal dominant trait and, in about 40% of patients, the causal mutation is identified in genes encoding sarcomere proteins. According to the results of genetic screening, HCM patients are currently categorized in two main sub-populations: sarcomeric-positive (Sarc+) patients, in whom the causal mutation is identified in a sarcomeric gene; and sarcomeric-negative (Sarc−) patients, in whom a causal mutation has not been identified. In rare cases, Sarc− HCM cases may be caused by pathogenic variants in non-sarcomeric genes. The aim of this review is to describe the differences in the phenotypic expression and clinical outcomes of Sarc+ and Sarc− HCM and to briefly discuss the current knowledge about HCM caused by rare non-sarcomeric mutations.

Targeting co-chaperones of HSP70 to modulate Myosin Binding Protein C turnover in hypertrophic cardiomyopathy.

Rationale: Hypertrophic Cardiomyopathy (HCM) is an inherited cardiovascular disease that affects 1 in 500 people. Over half of familial HCM cases arise from MyBP-C haploinsufficiency, thus stabilizing MyBP-C protein expression is an appealing therapeutic approach. Recently, two GWAS studies identified multiple HCM risk alleles. Three of the top 10 are localized near or in gene loci that code for HSP70 co-chaperones, highlighting the important role of the HSP70 system in HCM. Hypothesis: Co-chaperones of HSP70, (BAG3, DNAJC18, and HSPB7) regulate the expression and stability of sarcomeric and z-disc proteins, specifically MyBP-C. Methods/Results: Proximity labeling was performed to identify which components of the HSP70 co-chaperone network interact with or lie in close proximity to MyBP-C. Human iPSC-CMs (hiPSC-CMs) were transduced with a Turbo-ID-MYBPC3 adenoviral (AdV) construct, treated with biotin, and biotinylated proteins were captured by streptavidin beads. HSPA1A (i.e. HSP70), BAG3, DNAJC13, HSPB7, HSPB1, and CRYAB were identified by mass spectrometry as proximity proteins to wild-type MyBP-C but were absent in controls (AdV-MyBP-C without Turbo). hiPSC-CMs were transfected with AdV-shRNA to knock down HSP70 co-chaperone expression (BAG3, DNAJC18, or HSPB7). DNAJC18 was included because of the risk allele identified in GWAS, even though DNAJC18 was not identified as a direct interactor with MyBP-C during proximity labeling. Adv transfection efficiency was &gt; 70% (p&lt;0.0001) and resulted in a &gt;75% decrease (p&lt;0.01) in co-chaperone transcript expression and a &gt;50% decrease (p&lt;0.001) in protein. BAG3 knockdown decreased the steady state protein expression of MyBP-C (p&lt;0.0001) and a majority of other sarcomeric proteins. Utilizing a cycloheximide (CHX) chase assay to measure protein ½ life, MyBP-C protein degradation was greatly accelerated by BAG3 knockdown compared to scrambled shRNA 24 hours post-CHX (p&lt;0.0001). DNAJC18 knockdown had no significant effects on steady state protein expression of MyBP-C or other sarcomeric proteins, while HSPB7 knockdown increased MyBP-C (p&lt;0.01), myosin (p&lt;0.01), tropomyosin (p&lt;0.05), and myosin light chain 2 (p&lt;0.05) protein compared to scrambled shRNA. DNAJC18 and HSPB7 knockdown each increased BAG3 protein expression (p&lt;0.01), while BAG3 knockdown reduced DNAJC18 protein (p&lt;0.0001) but had no effect on HSPB7. Conclusion: MyBP-C interacts with and is stabilized by BAG3. MyBP-C may also be a direct client for HSPB7, but further studies are needed. Knockdown experiments of DNAJC13, HSBP1 and CRYAB, identified as proximity proteins of MyBP-C by Turbo-ID, are also underway. The HSP70 co-chaperone network may serve a therapeutic target to normalize MyBP-C levels in the context of MyBP-C haploinsufficiency. Institutional Start Up Funds This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hypertrophic cardiomyopathy is associated with dilated sinus of Valsalva: A case-control study.

We aimed to test the hypothesis that there is an association between hypertrophic cardiomyopathy and dilated aorta in a case-control, matched-design fashion. Of 65,843 studies done from November 2011 to December 2015, we found, after detailed evaluation by a single author, 153 cases of hypertrophic cardiomyopathy and 3,213 controls who were classified as normal clinically and echocardiographically. Controls were defined as normal patients referred to the echocardiography laboratory with no diagnoses and no known risk factors for dilated aorta (e.g., aortic stenosis, hypertension, aortic regurgitation). Clinical chart review showed none of the risk factors for dilated aorta, and echocardiography did not reveal any abnormalities. Of these 3,213 patients, 153 controls were matched to cases by age and sex by propensity score. Dilated aorta was defined according to clinical, Goldstein, and Lang's criteria. The prevalence of a dilated sinus of Valsalva was 9 times higher in hypertrophic cardiomyopathy patients than controls (OR = 9.4, P = 0.003). The 9-fold higher prevalence in hypertrophic cardiomyopathy patients persisted after adjusting for height, weight, and aortic pathology. Association of dilated mid-ascending aorta with hypertrophic cardiomyopathy was significant after adjustment for height and body surface area but became borderline insignificant after adjusting for weight and aortic valve pathology. Hypertrophic cardiomyopathy appears to be associated with a dilated sinus of Valsalva, even after adjusting for height, weight, and aortic valve pathology.

Apical Ischemia Is a Universal Feature of Apical Hypertrophic Cardiomyopathy.

Apical hypertrophic cardiomyopathy (ApHCM) accounts for ≈10% of hypertrophic cardiomyopathy cases and is characterized by apical hypertrophy, apical cavity obliteration, and tall ECG R waves with ischemic-looking deep T-wave inversion. These may be present even with <15 mm apical hypertrophy (relative ApHCM). Microvascular dysfunction is well described in hypertrophic cardiomyopathy. We hypothesized that apical perfusion defects would be common in ApHCM. A 2-center study using cardiovascular magnetic resonance short- and long-axis quantitative adenosine vasodilator stress perfusion mapping. One hundred patients with ApHCM (68 overt hypertrophy [≥15 mm] and 32 relative ApHCM) were compared with 50 patients with asymmetrical septal hypertrophy hypertrophic cardiomyopathy and 40 healthy volunteer controls. Perfusion was assessed visually and quantitatively as myocardial blood flow and myocardial perfusion reserve. Apical perfusion defects were present in all overt ApHCM patients (100%), all relative ApHCM patients (100%), 36% of asymmetrical septal hypertrophy hypertrophic cardiomyopathy, and 0% of healthy volunteers (P<0.001). In 10% of patients with ApHCM, perfusion defects were sufficiently apical that conventional short-axis views missed them. In 29%, stress myocardial blood flow fell below rest values. Stress myocardial blood flow was most impaired subendocardially, with greater hypertrophy or scar, and with apical aneurysms. Impaired apical myocardial blood flow was most strongly predicted by thicker apical segments (β-coefficient, -0.031 mL/g per min [CI, -0.06 to -0.01]; P=0.013), higher ejection fraction (-0.025 mL/g per min [CI, -0.04 to -0.01]; P<0.005), and ECG maximum R-wave height (-0.023 mL/g per min [CI, -0.04 to -0.01]; P<0.005). Apical perfusion defects are universally present in ApHCM at all stages. Its ubiquitous presence along with characteristic ECG suggests ischemia may play a disease-defining role in ApHCM.