scholarly journals Altered Intercellular Communication and Extracellular Matrix Signaling as a Potential Disease Mechanism in Human Hypertrophic Cardiomyopathy

2021 ◽  
Author(s):  
Amy Larson ◽  
Christina J Codden ◽  
Gordon S Huggins ◽  
Hassan Rastegar ◽  
Frederick Y Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Hypertrophic Cardiomyopathy ◽  
Intercellular Communication ◽  
Gene Expression Analysis ◽  
Left Ventricular Outflow Tract ◽  
Cell Types ◽  
Ventricular Outflow Tract ◽  
Left Ventricular ◽  
Left Ventricular Outflow

Objectives: To understand Hypertrophic Cardiomyopathy-associated alterations in gene expression and intercellular communication at the single cell level in left ventricular outflow tract lesions. Background: Human hypertrophic cardiomyopathy (HCM) is considered a disorder of the sarcomere (i.e., cardiomyocytes) but the paradoxical association of nonmyocyte phenotypes such as fibrosis, mitral valve anomalies and microvascular occlusion is unexplained. Methods: To understand the interplay between cardiomyocyte and nonmyocyte cell types in human HCM, single nuclei RNA-sequencing (snRNA-seq) was performed on myectomy specimens from HCM patients with left ventricular outflow tract obstruction and control samples from donor hearts free of cardiovascular disease. Results: Clustering analysis identified a total of 34 distinct cell populations, which were classified into 10 different cell types based on marker gene expression. Differential gene expression analysis comparing HCM to Normal datasets revealed differences in sarcomere and extracellular matrix gene expression. Analysis of expressed ligand-receptor pairs across multiple cell types indicated profound disruption in HCM intercellular communication, particularly between cardiomyocytes and fibroblasts, fibroblasts and lymphocytes and involving integrin β1 and its multiple extracellular matrix (ECM) cognate ligands. Conclusions: These findings provide evidence for intercellular interactions in HCM that link sarcomere dysfunction with altered cardiomyocyte secretion of ECM ligands, altered fibroblast ligand-receptor interactions with a variety of cell types and increased fibroblast to lymphocyte signaling, which can further alter the ECM composition, disrupt cellular function and promote nonmyocyte phenotypes.

scholarly journals Common and Distinctive Intercellular Communication Patterns in Human Obstructive and Nonobstructive Hypertrophic Cardiomyopathy

2021 ◽  
Author(s):  
Christina J. Codden ◽  
Michael T. Chin
Keyword(s):  
Extracellular Matrix ◽  
Hypertrophic Cardiomyopathy ◽  
Dendritic Cell ◽  
Differentially Expressed Genes ◽  
Intercellular Communication ◽  
Cell Communication ◽  
Cell Types ◽  
Ventricular Outflow Tract ◽  
Left Ventricular ◽  
Differentially Expressed

Hypertrophic Cardiomyopathy (HCM) is a common inherited disorder characterized by unexplained left ventricular hypertrophy, with or without left ventricular outflow tract (LVOT) obstruction. Single nuclei RNA-sequencing (snRNA-seq) of both obstructive and nonobstructive HCM patient samples have revealed alterations in communication between various cell types but a direct and integrated comparison between the two HCM phenotypes has not been reported. We performed a bioinformatic analysis of HCM snRNA-seq datasets from obstructive and nonobstructive patient samples to identify differentially expressed genes and distinctive patterns of intercellular communication. Differential gene expression analysis revealed 37 differentially expressed genes, predominantly in cardiomyocytes but also in other cell types, relevant to aging, muscle contraction, cell motility and the extracellular matrix. Intercellular communication was generally reduced in HCM, affecting the extracellular matrix, growth factor binding, integrin binding, PDGF binding and SMAD binding, but with increases in adenylate cyclase binding, calcium channel inhibitor activity, and serine-threonine kinase activity in nonobstructive HCM. Increases in neuron to leukocyte and dendritic cell communication, in fibroblast to leukocyte and dendritic cell communication and in endothelial cell communication to other cell types, largely through changes in expression of integrin-b1 and its cognate ligands, were also noted. These findings indicate both common and distinct physiological mechanisms affecting the pathogenesis of obstructive and nonobstructive HCM and provide opportunities for personalized management of different HCM phenotypes.

scholarly journals Common and Distinctive Intercellular Communication Patterns in Human Obstructive and Nonobstructive Hypertrophic Cardiomyopathy

2022 ◽  
Vol 23 (2) ◽  
pp. 946
Author(s):  
Christina J. Codden ◽  
Michael T. Chin
Keyword(s):  
Extracellular Matrix ◽  
Hypertrophic Cardiomyopathy ◽  
Dendritic Cell ◽  
Differentially Expressed Genes ◽  
Intercellular Communication ◽  
Cell Communication ◽  
Cell Types ◽  
Ventricular Outflow Tract ◽  
Left Ventricular ◽  
Differentially Expressed

Hypertrophic Cardiomyopathy (HCM) is a common inherited disorder characterized by unexplained left ventricular hypertrophy with or without left ventricular outflow tract (LVOT) obstruction. Single-nuclei RNA-sequencing (snRNA-seq) of both obstructive and nonobstructive HCM patient samples has revealed alterations in communication between various cell types, but no direct and integrated comparison between the two HCM phenotypes has been reported. We performed a bioinformatic analysis of HCM snRNA-seq datasets from obstructive and nonobstructive patient samples to identify differentially expressed genes and distinctive patterns of intercellular communication. Differential gene expression analysis revealed 37 differentially expressed genes, predominantly in cardiomyocytes but also in other cell types, relevant to aging, muscle contraction, cell motility, and the extracellular matrix. Intercellular communication was generally reduced in HCM, affecting the extracellular matrix, growth factor binding, integrin binding, PDGF binding, and SMAD binding, but with increases in adenylate cyclase binding, calcium channel inhibitor activity, and serine-threonine kinase activity in nonobstructive HCM. Increases in neuron to leukocyte and dendritic cell communication, in fibroblast to leukocyte and dendritic cell communication, and in endothelial cell communication to other cell types, largely through changes in the expression of integrin-β1 and its cognate ligands, were also noted. These findings indicate both common and distinct physiological mechanisms affecting the pathogenesis of obstructive and nonobstructive HCM and provide opportunities for the personalized management of different HCM phenotypes.

Angina Pectoris Due to Severe Muscular Bridge in Hypertrophic Cardiomyopathy

1998 ◽  
Vol 6 (2) ◽  
pp. 132-134
Author(s):  
M Şah Topcuoĝlu ◽  
Ayhan Usal ◽  
Cem Kayhan ◽  
Aladdin Pekedis ◽  
Acar Tokcan ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Calcium Antagonist ◽  
Hypertrophic Cardiomyopathy ◽  
Angina Pectoris ◽  
Left Ventricular Outflow Tract ◽  
Young Patients ◽  
Ventricular Outflow Tract ◽  
Myocardial Scintigraphy ◽  
Left Ventricular ◽  
Left Ventricular Outflow

We report the case of a 39-year-old male with hypertrophic cardiomyopathy who complained of angina pectoris. The patient was treated with a beta blocker and a calcium antagonist without effect. Myocardial scintigraphy revealed anterior ischemia. Cardiac catheterization and ventriculography revealed severe systolic narrowing of the left anterior descending coronary artery and no significant pressure gradient across the left ventricular outflow tract. Myotomy was performed on a muscular bridge over the left anterior descending coronary artery and the patient's angina was relieved. In young patients with hypertrophic cardiomyopathy who develop angina refractory to medical therapy, a coexisting muscular bridge should be sought.

scholarly journals Characteristics and Outcomes of Elderly Patients With Hypertrophic Cardiomyopathy

2021 ◽  
Vol 10 (3) ◽  
Author(s):  
Alaa Alashi ◽  
Nicholas G. Smedira ◽  
Zoran B. Popovic ◽  
Agostina Fava ◽  
Maran Thamilarasan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Hypertrophic Cardiomyopathy ◽  
Elderly Patients ◽  
Left Ventricular Outflow Tract ◽  
Ventricular Outflow Tract ◽  
Left Ventricular ◽  
Outflow Tract ◽  
Alcohol Ablation ◽  
Left Ventricular Outflow ◽  
Sudden Cardiac Death Risk

Background We report characteristics and outcomes of elderly patients with hypertrophic cardiomyopathy (HCM) with basal septal hypertrophy and dynamic left ventricular outflow tract obstruction. Methods and Results We studied 1110 consecutive elderly patients with HCM (excluding moderate or greater aortic stenosis or subaortic membrane, age 80±5 years [range, 75–92 years], 66% women), evaluated at our center between June 2002 and December 2018. Clinical and echocardiographic data, including maximal left ventricular outflow tract gradient, were recorded. The primary outcome was death and appropriate internal defibrillator discharge. Hypertension was observed in 72%, with a Society of Thoracic Surgeons (STS) score (8.6±6); while 80% had no HCM‐related sudden cardiac death risk factors. Left ventricular mass index, basal septal thickness, and maximal left ventricular outflow tract gradient were 127±43 g/m 2 , 1.7±0.4 cm, and 49±31 mm Hg, respectively. A total of 597 (54%) had a left ventricular outflow tract gradient >30 mm Hg, of which 195 (33%) underwent septal reduction therapy (SRT; 79% myectomy and 21% alcohol ablation). At 5.1±4 years, 556 (50%) had composite events (273 [53%] in nonobstructive, 220 [55%] in obstructive without SRT, and 63 [32%] in obstructive subgroup with SRT). One‐ and 5‐year survival, respectively were 93% and 63% in nonobstructive, 90% and 63% in obstructive subgroup without SRT, and 94% and 84% in the obstructive subgroup with SRT. Following SRT, there were 5 (2.5%) in‐hospital deaths (versus an expected Society of Thoracic Surgeons mortality of 9.2%). Conclusions Elderly patients with HCM have a high prevalence of traditional cardiovascular rather than HCM risk factors. Longer‐term outcomes of the obstructive SRT subgroup were similar to a normal age‐sex matched US population.

Abstract 13729: Surgical Myectomy Results in Significantly Improved Long-term Event Rate in Hypertrophic Cardiomyopathy Patients With Severe Left Ventricular Outflow Tract Obstruction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Milind Y Desai ◽  
Nicholas G Smedira ◽  
Aditya Bhonsale ◽  
Nitesh Ainani ◽  
Maran THamilarasan ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Left Ventricular Outflow Tract ◽  
Ventricular Outflow Tract ◽  
Left Ventricular ◽  
Outflow Tract ◽  
Long Term Outcomes ◽  
Free Survival ◽  
Left Ventricular Outflow ◽  
Surgical Myectomy

Background: In hypertrophic cardiomyopathy (HCM) with severe left ventricular outflow tract obstruction (LVOTO), surgical myectomy (SM) performed for relief of intractable symptoms is safe and associated with excellent long-term symptom-free survival. In such patients, we sought to determine if SM also results in improvement of long-term outcomes. Methods: We studied 1530 HCM patients with severe LVOTO (50±13 years, 63% men) that were evaluated at our center [excluding <18 years of age, LV ejection fraction (LVEF) <50%, LVOT gradient <30 mm Hg). Clinical, echocardiographic and surgical data were recorded. A composite endpoint of death and/or implantable defibrillator (ICD) discharge was recorded. Results: Hypertension, coronary artery disease (CAD), family history of HCM and syncope were present in 41%, 15%, 17% and 18%, while 73% patients were in Functional Class (FC) ≥ II. Mean LVEF, basal septal thickness, LVOT gradient (resting or provocable) and indexed left atrial dimensions were 62±5%, 2.2±1 cm, 101±39 mm Hg, 2.2±0.4 cm/m2. During 8±6 years of follow-up, 990 (65%) patients underwent SM (of which 65% were isolated SM), while 540 (35%) did not. 94 (6%) patients had alcohol septal ablation (66 in the non myectomy group), while 18% developed atrial fibrillation (AF), and 18% had ICD. There were 169 (11%) events (151 deaths), with 0% 30-day mortality in the SM group. On stepwise multivariable Cox Proportional Hazard analysis, increasing age (Hazard Ratio or HR 1.22 [1.06-1.40]), CAD (HR 1.57 [1.06-2.33]), worsening FC (HR 1.34 [1.05-1.71]) and AF (HR 1.73 [1.23-2.43]) predicted higher events, while SM as a time-dependent covariate (HR 0.58 [0.41-0.81]) was associated with improved event-free survival (all p<0.01). Kaplan-Meier curve showing impact of SM on outcomes is shown in Figure. Conclusion: In HCM patients with severe LVOTO, SM is associated with significant improvement in long-term outcomes when compared to watchful waiting.

scholarly journals Assessment of myocardial function in obstructive hypertrophic cardiomyopathy cats with and without response to medical treatment by carvedilol

2019 ◽  
Vol 15 (1) ◽  
Author(s):  
Ryohei Suzuki ◽  
Yohei Mochizuki ◽  
Yunosuke Yuchi ◽  
Yuyo Yasumura ◽  
Takahiro Saito ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Treatment Response ◽  
Myocardial Function ◽  
Left Ventricular Outflow Tract ◽  
Beta Blockers ◽  
Ventricular Outflow Tract ◽  
Left Ventricular ◽  
Outflow Tract ◽  
Obstructive Hypertrophic Cardiomyopathy ◽  
Left Ventricular Outflow

Abstract Background Inconsistency of treatment response in cats with obstructive hypertrophic cardiomyopathy is well recognized. We hypothesized that the difference in response to beta-blockers may be caused by myocardial functional abnormalities. This study was designed to compare myocardial function in cats with obstructive hypertrophic cardiomyopathy with and without response to beta-blockers. Twenty-one, client-owned, hypertrophic cardiomyopathy cats treated with carvedilol were analyzed. After carvedilol treatment, cats with decreased left ventricular outflow tract velocity were categorized as responders (n = 10); those exhibiting no response (no decrease in the left ventricular outflow tract velocity) were categorized as non-responders (n = 11). The cats were examined using layer-specific assessment of the myocardial function (whole, endocardial, and epicardial layers) longitudinally and circumferentially by two-dimensional speckle-tracking echocardiography, before and after carvedilol treatment. Results The non-responder cats had a significantly higher age, end-diastolic left ventricular posterior-wall thickness, peak velocity of left ventricular outflow tract, and dose of carvedilol than the responders (p = 0.04, p < 0.01, p < 0.01, and p < 0.01, respectively). The circumferential strain in the epicardial layer was lower and circumferential endocardial to epicardial strain ratio was higher in non-responders than responders (p < 0.001 and p = 0.006). According to the multivariate analysis, circumferential strain in the epicardial layer was the only independent correlate of treatment response with carvedilol. Conclusions Myocardial function, assessed by two-dimensional speckle-tracking echocardiography, differed in cats with hypertrophic cardiomyopathy with and without response to beta-blockers. The determination of layer-specific myocardial function may facilitate detailed pathophysiologic assessment and treatment response in cats with hypertrophic cardiomyopathy.

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