scholarly journals Ion Channel Impairment and Myofilament Ca2+ Sensitization: Two Parallel Mechanisms Underlying Arrhythmogenesis in Hypertrophic Cardiomyopathy

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2789
Author(s):  
Lorenzo Santini ◽  
Raffaele Coppini ◽  
Elisabetta Cerbai
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Ventricular Arrhythmias ◽  
Early Stage ◽  
Sodium Current ◽  
Young Patients ◽  
Early Observation ◽  
Parallel Mechanisms ◽  
Cellular Mechanisms ◽  
Increased Risk ◽  
Repolarization Reserve

Life-threatening ventricular arrhythmias are the main clinical burden in patients with hypertrophic cardiomyopathy (HCM), and frequently occur in young patients with mild structural disease. While massive hypertrophy, fibrosis and microvascular ischemia are the main mechanisms underlying sustained reentry-based ventricular arrhythmias in advanced HCM, cardiomyocyte-based functional arrhythmogenic mechanisms are likely prevalent at earlier stages of the disease. In this review, we will describe studies conducted in human surgical samples from HCM patients, transgenic animal models and human cultured cell lines derived from induced pluripotent stem cells. Current pieces of evidence concur to attribute the increased risk of ventricular arrhythmias in early HCM to different cellular mechanisms. The increase of late sodium current and L-type calcium current is an early observation in HCM, which follows post-translation channel modifications and increases the occurrence of early and delayed afterdepolarizations. Increased myofilament Ca2+ sensitivity, commonly observed in HCM, may promote afterdepolarizations and reentry arrhythmias with direct mechanisms. Decrease of K+-currents due to transcriptional regulation occurs in the advanced disease and contributes to reducing the repolarization-reserve and increasing the early afterdepolarizations (EADs). The presented evidence supports the idea that patients with early-stage HCM should be considered and managed as subjects with an acquired channelopathy rather than with a structural cardiac disease.

scholarly journals Prolonged QT Interval in a Patient With Coronavirus Disease-2019: Beyond Hydroxychloroquine and Azithromycin

2020 ◽  
Vol 8 ◽  
pp. 232470962094840
Author(s):  
B K Anupama ◽  
Soumya Adhikari ◽  
Debanik Chaudhuri
Keyword(s):  
Qt Interval ◽  
Ventricular Arrhythmias ◽  
Torsade De Pointes ◽  
Cardiac Pacing ◽  
Qt Prolongation ◽  
Medication Effects ◽  
Increased Risk ◽  
Repolarization Reserve ◽  
Prolonged Qt Interval ◽  
Prolonged Qt

Recent reports have suggested an increased risk of QT prolongation and subsequent life-threatening ventricular arrhythmias, particularly torsade de pointes, in patients with coronavirus disease-2019 (COVID-19) treated with hydroxychloroquine and azithromycin. In this article, we report the case of a 75-year-old female with a baseline prolonged QT interval in whom the COVID-19 illness resulted in further remarkable QT prolongation (>700 ms), precipitating recurrent self-terminating episodes of torsade de pointes that necessitated temporary cardiac pacing. Despite the correction of hypoxemia and the absence of reversible factors, such as adverse medication effects, electrolyte derangements, and usage of hydroxychloroquine/azithromycin, the QT interval remained persistently prolonged compared with the baseline with subsequent degeneration into ventricular tachycardia and death. Thus, we highlight that COVID-19 illness itself can potentially lead to further prolongation of QT interval and unmask fatal ventricular arrhythmias in patients who have a prolonged QT and low repolarization reserve at baseline.

Abstract 14117: Clinical Characteristics and Cardiovascular Outcomes in Childhood-Onset Hypertrophic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Nicholas A Marston ◽  
Larry Han ◽  
iacopo olivotto ◽  
Sharlene Day ◽  
Euan A Ashley ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Ventricular Arrhythmias ◽  
Composite Endpoint ◽  
Adult Onset ◽  
Childhood Onset ◽  
Ventricular Assist ◽  
Disease Biology ◽  
Increased Risk ◽  
Age Of Diagnosis ◽  
Life Threatening

Introduction: The prevalence of childhood-onset hypertrophic cardiomyopathy (HCM) is lower than adult-onset disease, thus natural history is not well characterized. We aim to describe the characteristics and outcomes of childhood-onset HCM. Methods: We performed an observational cohort study of 6345 HCM patients from the Sarcomeric Human Cardiomyopathy Registry (SHaRe) and Toronto's SickKids hospital. HCM patients were stratified by age at diagnosis (<1 year (infancy), 1-18 years (childhood), >18 years (adulthood)) and assessed for composite endpoints reflecting heart failure (HF), life-threatening ventricular arrhythmias, atrial fibrillation (AF), and an overall composite that also included stroke and death. Results: Based on defined age of diagnosis stratification, 173 (3%) patients were diagnosed in infancy, 909 (14%) in childhood, and 5263 (83%) in adulthood. Childhood-onset HCM patients had a 2%/year event rate for the overall composite endpoint, with ventricular arrhythmias representing the most common event in the 1st decade following diagnosis, and HF and AF more common by the end of the 2nd decade ( Fig, a ). Sarcomeric HCM was more common in childhood-onset HCM (62%) and carried a worse prognosis than non-sarcomeric disease, including a >2-fold increased risk of HF (HR adj 2.39 [1.36-4.20], p=0.003) and 67% increased risk of overall composite events (HR adj 1.67 [1.16-2.41], p=0.006). When compared to adult-onset HCM, childhood-onset was 36% more likely to develop life-threatening ventricular arrhythmias (HR adj 1.36 [1.03-1.80]) and twice as likely to require transplant or ventricular assist device (HR adj 1.99 [1.23-3.23]) ( Fig, b ). Conclusion: Patients with childhood-onset HCM are more likely to have sarcomeric disease, carry higher risk of life-threatening ventricular arrythmias, and have greater need for advanced HF therapies. These findings provide insight into disease biology and can help improve the precision of risk prediction.

scholarly journals Factors associated with increased risk of sudden death in young patients with hypertrophic cardiomyopathy

2003 ◽  
Vol 41 (6) ◽  
pp. 147
Author(s):  
Dorothea McAreavey ◽  
Jeffrey P. Moak ◽  
Dorothy Tripodi ◽  
Saidi A. Mohiddin ◽  
Rose M. Wienhoff ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Sudden Death ◽  
Young Patients ◽  
Factors Associated ◽  
Increased Risk

scholarly journals Clinical characteristics and outcomes in childhood-onset hypertrophic cardiomyopathy

2021 ◽  
Author(s):  
Nicholas A Marston ◽  
Larry Han ◽  
Iacopo Olivotto ◽  
Sharlene M Day ◽  
Euan A Ashley ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Natural History ◽  
Ventricular Arrhythmias ◽  
Composite Endpoint ◽  
Adult Onset ◽  
Childhood Onset ◽  
Ventricular Assist ◽  
Increased Risk ◽  
Age Of Diagnosis ◽  
Life Threatening

Abstract Aims Childhood-onset hypertrophic cardiomyopathy (HCM) is far less common than adult-onset disease, thus natural history is not well characterized. We aim to describe the characteristics and outcomes of childhood-onset HCM. Methods and results We performed an observational cohort study of 7677 HCM patients from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Hypertrophic cardiomyopathy patients were stratified by age at diagnosis [&lt;1 year (infancy), 1–18 years (childhood), &gt;18 years (adulthood)] and assessed for composite endpoints reflecting heart failure (HF), life-threatening ventricular arrhythmias, atrial fibrillation (AF), and an overall composite that also included stroke and death. Stratifying by age of diagnosis, 184 (2.4%) patients were diagnosed in infancy; 1128 (14.7%) in childhood; and 6365 (82.9%) in adulthood. Childhood-onset HCM patients had an ∼2%/year event rate for the overall composite endpoint, with ventricular arrhythmias representing the most common event in the 1st decade following baseline visit, but HF and AF becoming more common by the end of the 2nd decade. Sarcomeric variants were more common in childhood-onset HCM (63%) and carried a worse prognosis than non-sarcomeric disease, including a greater than two-fold increased risk of HF [HRadj 2.39 (1.36–4.20), P = 0.003] and 67% increased risk of the overall composite outcome [HRadj 1.67 (1.16–2.41), P = 0.006]. When compared with adult-onset HCM, childhood-onset was 36% more likely to develop life-threatening ventricular arrhythmias [HRadj 1.36 (1.03–1.80)] and twice as likely to require transplant or ventricular assist device [HRadj 1.99 (1.23–3.23)]. Conclusion Patients with childhood-onset HCM are more likely to have sarcomeric disease, carry a higher risk of life-threatening ventricular arrythmias, and have greater need for advanced HF therapies. These findings provide insight into the natural history of disease and can help inform clinical risk stratification.

scholarly journals Familial Factors Predispose to Increased Risk of Ventricular Arrhythmias in Patients with Hypertrophic Cardiomyopathy

2019 ◽  
Vol 28 ◽  
pp. S138
Author(s):  
F. Stafford ◽  
A. Butters ◽  
C. Burns ◽  
C. Medi ◽  
C. Semsarian ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Ventricular Arrhythmias ◽  
Familial Factors ◽  
Increased Risk

scholarly journals Contemporary Locoregional Recurrence Rates in Young Patients With Early-Stage Breast Cancer

2016 ◽  
Vol 34 (18) ◽  
pp. 2107-2114 ◽  
Author(s):  
Kim C. Aalders ◽  
Emily L. Postma ◽  
Luc J. Strobbe ◽  
Margriet van der Heiden-van der Loo ◽  
Gabe S. Sonke ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Early Stage ◽  
Tumor Biology ◽  
Young Patients ◽  
Early Stage Breast Cancer ◽  
Her2 Positive ◽  
Entire Study ◽  
Netherlands Cancer Registry ◽  
Increased Risk

Purpose The aim of this study was to evaluate contemporary rates of local recurrence (LR) and regional recurrence (RR) in young patients with breast cancer in relation to tumor biology as expressed by biomarker subtypes. Patients and Methods Women < 35 years of age who underwent surgery for primary unilateral invasive breast cancer between 2003 and 2008 were selected from the Netherlands Cancer Registry. Patients were categorized according to biomarker subtypes on the basis of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. The 5-year risks of developing LR and regional lymph node recurrence were estimated by using Kaplan-Meier statistics. Results A total of 1,000 patients were identified, of whom 59% had a known subtype: 39% HR-positive/HER2-negative; 17% HR-positive/HER2-positive; 10% HR-negative/HER2-positive; and 34% HR-negative/HER2-negative (triple negative). Overall 5-year LR and RR rates were 3.5% and 3.7%, respectively. A decreasing trend for both rates was observed over time and was accompanied by a significant decrease in the risk of distant metastases (DM). LR occurred in 4.2%, RR in 6.1%, and DM in 17.8% of patients in 2003, and in 3.2%, 4.4%, and 10.0%, respectively, in 2008. LR and RR rates varied with biomarker subtype. These differences were borderline significant when analyzed for the entire study period (P = .056 and P = .014, respectively) and leveled off after the introduction of trastuzumab after 2005 (P = .24 and P = .42, respectively). Patients with lymph node metastases at the time of diagnosis had an increased risk of RR. The type of surgery performed—breast-conserving or mastectomy—did not influence rates of LR and RR. Conclusion Overall, the rates of LR and RR in young patients with early-stage breast cancer were relatively low and varied by biomarker subtype.

Advanced imaging for risk stratification of sudden death in hypertrophic cardiomyopathy

Heart ◽  
2020 ◽  
Vol 106 (11) ◽  
pp. 793-801 ◽  
Author(s):  
Jay Ramchand ◽  
Agostina M Fava ◽  
Michael Chetrit ◽  
Milind Y Desai
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Risk Stratification ◽  
Ventricular Arrhythmias ◽  
Left Ventricular ◽  
Small Subset ◽  
Imaging Features ◽  
Icd Implantation ◽  
Increased Risk ◽  
Cardiac Condition

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac condition, which typically manifests as left ventricular hypertrophy. A small subset of patients with HCM have an increased risk of sudden cardiac death (SCD) from ventricular arrhythmias. Risk of SCD can be effectively reduced following implantation of implantable cardiac defibrillators (ICD), although this treatment carries a risk of complications such as inappropriate shocks. With this in mind, we turn to advances in cardiac imaging to guide risk stratification for SCD and to select the appropriate individual who may benefit from ICD implantation. In this review, we have taken the opportunity to briefly summarise the role of imaging in the diagnosis of HCM before focusing on how specific imaging features influence risk of SCD in patients with HCM.

scholarly journals Abnormalities in sodium current and calcium homoeostasis as drivers of arrhythmogenesis in hypertrophic cardiomyopathy

2020 ◽  
Vol 116 (9) ◽  
pp. 1585-1599
Author(s):  
Raffaele Coppini ◽  
Lorenzo Santini ◽  
Iacopo Olivotto ◽  
Michael J Ackerman ◽  
Elisabetta Cerbai
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Sodium Current ◽  
Phenotypic Expression ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Monogenic Disease ◽  
Ventricular Tachyarrhythmias ◽  
Clinical Markers ◽  
Cellular Mechanisms ◽  
Cellular Models

Abstract Hypertrophic cardiomyopathy (HCM) is a common inherited monogenic disease with a prevalence of 1/500 in the general population, representing an important cause of arrhythmic sudden cardiac death (SCD), heart failure, and atrial fibrillation in the young. HCM is a global condition, diagnosed in &gt;50 countries and in all continents. HCM affects people of both sexes and various ethnic and racial origins, with similar clinical course and phenotypic expression. The most unpredictable and devastating consequence of HCM is represented by arrhythmic SCD, most commonly caused by sustained ventricular tachycardia or ventricular fibrillation. Indeed, HCM represents one of the main causes of arrhythmic SCD in the young, with a marked preference for children and adults &lt;30 years. SCD is most prevalent in patients with paediatric onset of HCM but may occur at any age. However, risk is substantially lower after 60 years, suggesting that the potential for ventricular tachyarrhythmias is mitigated by ageing. SCD had been linked originally to sports and vigorous activity in HCM patients. However, it is increasingly clear that the majority of events occurs at rest or during routine daily occupations, suggesting that triggers are far from consistent. In general, the pathophysiology of SCD in HCM remains unresolved. While the pathologic and physiologic substrates abound and have been described in detail, specific factors precipitating ventricular tachyarrhythmias are still unknown. SCD is a rare phenomenon in HCM cohorts (&lt;1%/year) and attempts to identify patients at risk, while generating clinically useful algorithms for primary prevention, remain very inaccurate on an individual basis. One of the reasons for our limited understanding of these phenomena is that limited translational research exists in the field, while most efforts have focused on clinical markers of risk derived from pathology, instrumental patient evaluation, and imaging. Specifically, few studies conducted in animal models and human samples have focused on targeting the cellular mechanisms of arrhythmogenesis in HCM, despite potential implications for therapeutic innovation and SCD prevention. These studies found that altered intracellular Ca2+ homoeostasis and increased late Na+ current, leading to an increased likelihood of early and delayed after-depolarizations, contribute to generate arrhythmic events in diseased cardiomyocytes. As an array of novel experimental opportunities have emerged to investigate these mechanisms, including novel ‘disease-in-the-dish’ cellular models with patient-specific induced pluripotent stem cell-derived cardiomyocytes, important gaps in knowledge remain. Accordingly, the aim of the present review is to provide a contemporary reappraisal of the cellular basis of SCD-predisposing arrhythmias in patients with HCM and discuss the implications for risk stratification and management.

scholarly journals Risk Stratification in Hypertrophic Cardiomyopathy

2015 ◽  
Vol 10 (1) ◽  
pp. 31 ◽  
Author(s):  
Alexandros Klavdios Steriotis ◽  
Sanjay Sharma ◽  
◽  
Keyword(s):  
Risk Factors ◽  
Hypertrophic Cardiomyopathy ◽  
Risk Stratification ◽  
Ventricular Arrhythmias ◽  
Risk Model ◽  
Predictive Accuracy ◽  
Young Patients ◽  
Left Ventricular ◽  
Adverse Event Rate ◽  
Icd Implantation

Hypertrophic cardiomyopathy (HCM) is a hereditary primary myocardial disease that is most commonly due to mutations within genes encoding sarcomeric contractile proteins and is characterised by left ventricular hypertrophy in the absence of a cardiac or systemic cause. Although the overall prognosis is relatively good with an annual mortality rate <1 %, the propensity to potentially fatal ventricular arrhythmias is the most feared complication. The identification of patients at risk of arrhythmogenic sudden cardiac death (SCD) is an essential component in disease management. Aborted SCD and malignant ventricular arrhythmias are the most powerful risk factors for SCD and ICD implantation is recommended in such circumstances. The selection of patients who may benefit from ICD therapy for primary prevention purposes is more challenging. The heterogeneous nature of the disease and the variation in trigger factors provides an adequate explanation for the low predictive accuracy of most conventional risk factors in isolation. A new risk model for risk stratification proposed by the European Society of Cardiology HCM outcome group shows promise but requires validation in different cohorts. The ICD is the only effective therapy in preventing SCD for the disease with a relatively low adverse event rate, but most deaths occur in relatively young patients. However, it is also difficult to ignore the complications with the ICD, therefore, the strive to perfect risk stratification in HCM should continue to ensure that only the most high-risk patients receive an ICD.

Myocardial Noncompaction

2018 ◽  
Vol 69 (8) ◽  
pp. 2209-2212
Author(s):  
Alexandru Radu Mihailovici ◽  
Vlad Padureanu ◽  
Carmen Valeria Albu ◽  
Venera Cristina Dinescu ◽  
Mihai Cristian Pirlog ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Specific Treatment ◽  
Left Ventricular ◽  
Left Ventricular Noncompaction ◽  
Ventricular Noncompaction ◽  
Genetic Transmission ◽  
Asymptomatic Patients ◽  
Increased Risk ◽  
Patients With Heart Failure

Left ventricular noncompaction is a primary cardiomyopathy with genetic transmission in the vast majority of autosomal dominant cases. It is characterized by the presence of excessive myocardial trabecularities that generally affect the left ventricle. In diagnosing this condition, echocardiography is the gold standard, although this method involves an increased risk of overdiagnosis and underdiagnosis. There are also uncertain cases where echocardiography is inconclusive, a multimodal approach is needed, correlating echocardiographic results with those obtained by magnetic resonance imaging. The clinical picture may range from asymptomatic patients to patients with heart failure, supraventricular or ventricular arrhythmias, thromboembolic events and even sudden cardiac death. There is no specific treatment of left ventricular noncompaction, but the treatment is aimed at preventing and treating the complications of the disease. We will present the case of a young patient with left ventricular noncompactioncardiomyopathy and highlight the essential role of transthoracic echocardiography in diagnosing this rare heart disease.

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