Sudden Death In Hypertrophic Cardiomyopathy Research Articles

An In Silico Cardiomyocyte Reveals the Impact of Changes in CaMKII Signalling on Cardiomyocyte Contraction Kinetics in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterised by asymmetric left ventricular hypertrophy, ventricular arrhythmias, and cardiomyocyte dysfunction that may cause sudden death. HCM is associated with mutations in sarcomeric proteins and is usually transmitted as an autosomal-dominant trait. The aim of this in silico study was to assess the mechanisms that underlie the altered electrophysiological activity, contractility, regulation of energy metabolism, and crossbridge cycling in HCM at the single-cell level. To investigate this, we developed a human ventricular cardiomyocyte model that incorporates electrophysiology, metabolism, and force generation. The model was validated by its ability to reproduce the experimentally observed kinetic properties of human HCM induced by (a) remodelling of several ion channels and Ca2+-handling proteins arising from altered Ca2+/calmodulin kinase II signalling pathways and (b) increased Ca2+ sensitivity of the myofilament proteins. Our simulation showed a decreased phosphocreatine-to-ATP ratio (-9%) suggesting a negative mismatch between energy expenditure and supply. Using a spatial myofilament half-sarcomere model, we also compared the fraction of detached, weakly bound, and strongly bound crossbridges in the control and HCM conditions. Our simulations showed that HCM has more crossbridges in force-producing states than in the control condition. In conclusion, our model reveals that impaired crossbridge kinetics is accompanied by a negative mismatch between the ATP supply and demand ratio. This suggests that improving this ratio may reduce the incidence of sudden death in HCM.

Remote monitoring of cardiac implantable devices in children: characteristics and outcome in a retrospective single centre contemporary study. TelePaedia study

Abstract Introduction Remote monitoring (RM) has revolutionized implantable cardiac device care in adults. It has demonstrated its safety on hard criteria, a reduction in the number of hospitalizations and emergency room visits, early detection of events and a reduction in inappropriate therapies. However, while pediatric population is becoming emerging, particularly considering congenital heart diseases, there is no contemporary study. Objective The aim of our study was to characterize in our cohort of RM patients the population of children (below 18 yo) implanted with a pacemaker or an ICD and under RM for more than 1 year. Method The data collection was carried out retrospectively within the cohort of RM patients at our university hospital. The outcome combined occurrence of ventricular (VT)/supraventricular (SVT) arrhythmias, appropriate or inappropriate therapies, lead dysfunction/fracture and ERI. Results The study population included 34 patients (17F/17M) with a mean age of 9.4+/-5.8 years (range 0-18 yo) and a mean remote follow-up of 4.6+/-3.9 years (range 1-13 y). The indications for pacing were postoperative atrioventricular block (AVB, n = 9) for operated congenital heart disease or hypertrophic cardiomyopathy (n=1), congenital AVB (n= 5), muscular dystrophy (n = 1) and genetic sinus node dysfunction (n = 1). Indications for an ICD were resuscitated sudden death in hypertrophic cardiomyopathy (n = 4), LQTS (n = 5), CPVT (n = 2), arrhythmogenic right ventricular dysplasia (n = 2), Brugada syndrome (n = 1) and congenital heart disease (n = 2). Pacing devices (n = 17) were mostly implanted with epicardial leads and abdominal box (n = 12). ICDs (n = 18) were implanted in primary (n = 4) or in secondary prevention with epicardial (n = 2)/ endovascular (n=9) /subcutaneous (n = 2) leads depending on children weight and anatomy. One 12 yo-boy had an S-ICD in addition to a previous pacemaker. There were a total of 13 patients with device-triggered alerts: VT in 8 including appropriate therapies in 6 and inappropriate shocks in 2, supraventricular tachycardia in 2, RV lead dysfunction in 2, RV lead fracture in 1 and no alert for ERI. All alerts were treated within 24h. Conclusion This is the first report of cardiac device remote monitoring in a pediatric population. In our population 13/34 patients experienced alerts necessitating intervention over a mean 4.6 year-follow-up. Remote monitoring through device-triggered alerts allowed efficient treatment of an arrhythmic event or a lead dysfunction. This is a preliminary study suggesting the need for further studies on a larger population. Remote monitoring should be considered in all eligible-device children and should be considered as standard of care.

Abstract 14304: Does QRS Fragmentation Have a Role in Risk Stratification for Sudden Death in Hypertrophic Cardiomyopathy?

Background: Fragmentation of the QRS complex on 12-lead electrocardiogram (ECG) represents alterations of myocardial activation due to myocardial scarring and has been associated with increased risk for sudden death and adverse prognosis. However the clinical significance of this finding in hypertrophic cardiomyopathy (HCM) remains unresolved. Methods: Consecutive HCM patients evaluated from 2004 to 2020 were included and followed for 5.1 ± 4.1 years for outcomes including sudden death events (appropriate ICD interventions for VT/VF, cardiac arrest, or sudden death) and development of endstage heart failure requiring transplant. QRS fragmentation was defined as presence of an additional R wave or notching in the R or S wave in two contiguous ECG leads in the absence of bundle branch block. Results: Among 1929 HCM patients, 539 (28%) were identified with QRS fragmentation. As compared to patients without QRS fragmentation, patients with QRS fragmentation had similar baseline demographics including age (52±16 vs. 53±16, p=0.35), gender (60% vs. 61% male, p=0.51), ejection fraction (64 ± 6 vs. 64 ± 5, p=0.77) and presence of LV outflow obstruction (≥30mmHg at rest or provocation; 65% vs. 65%, p=0.9). While patients with QRS fragmentation had more substantial LV hypertrophy (19 ± 4 vs. 18 ± 4, p=0.001) as well as presence and extent of late gadolinium enhancement by cardiac MRI (64% vs. 56%, 6.3 ± 6 vs. 5 ± 5, p<0.01), there was no difference in other risk markers including syncope (9% vs 9%, p=0.89), family history of SD (8% vs. 6%, p=0.31), NSVT (10.5% vs. 8%, p=0.10). Over follow-up, patients with QRS fragmentation were at increased risk for sudden death events (5.6% vs. 2.2%, p<0.001) and development of end-stage heart failure requiring transplant (2.4% vs. 0.8%, p=0.007). However, sensitivity and positive predictive value of QRS fragmentation for predicting sudden death events (50% and 5.6%, respectively) as well as endstage heart failure (52% and 2.4%) is limited. Conclusion: In a large consecutive HCM cohort, QRS fragmentation on 12-lead ECG is associated with extreme HCM phenotype and a number of adverse consequences including sudden death events and endstage development, and represents a potential prognostic marker.

Effect of Renal Dysfunction on Risk of Sudden Cardiac Death in Patients With Hypertrophic Cardiomyopathy

Renal dysfunction is a known risk of sudden cardiac death in patients with ischemic heart disease. However, the association between renal dysfunction and sudden death in hypertrophic cardiomyopathy (HC) patients remains unknown. This study investigated the significance of an impaired renal function for the sudden death risk in a cohort of patients with HC. We included 450 patients with HC (mean age 52.9 years, 65.1% men). The estimated glomerular filtration rate (eGFR) was evaluated at the time of the initial evaluation. Renal dysfunction was defined as an eGFR <60 ml/min/1.73 m2. Renal dysfunction was found in 171 patients (38.0%) at the time of enrollment. Over a median (IQR) follow-up period of 8.8 (5.0 to 12.5) years, 56 patients (12.4%) experienced the combined end point of sudden death or potentially lethal arrhythmic events, including 20 with sudden death (4.4%), 11 resuscitated after a cardiac arrest, and 25 with appropriate implantable defibrillator shocks. Patients with renal dysfunction were at a significantly higher risk of sudden death (Log-rank p = 0.034) and the combined end point (Log-rank p <0.001) than patients without renal dysfunction. After adjusting for the highly imbalanced baseline variables, the eGFR remained as an independent correlate of the combined end point (adjusted hazard ratio: 1.24 per 10 ml/min decline in the eGFR; 95% confidence interval 1.04 to 1.47; p = 0.013). In conclusion, an impaired renal function may be associated with an incremental risk of sudden death or potentially lethal arrhythmic events in patients with HC.

Back to the future: Predicting sudden death in hypertrophic cardiomyopathy relying on individual risk markers and physician judgment without mathematical scoring

Back to the future: Predicting sudden death in hypertrophic cardiomyopathy relying on individual risk markers and physician judgment without mathematical scoring

Arrhythmias and Sudden Death Risk in Hypertrophic Cardiomyopathy

The risk of sudden death in hypertrophic cardiomyopathy is related to the presence of ventricular arrhythmias in most cases. Finding the best schemes to assess the probability of arrhythmic complications will remain a challenge for modern Cardiology. Meanwhile, the multifactorial approach is the best strategy to avoid the unnecessary implantation of devices such as the implantable cardioverter defibrillator. Although the electrocardiogram remains an excellent diagnostic tool, even before echocardiographic expression, it does not have a clear role as a risk factor. However, the identification of associated arrhythmias such as preexcitation or long QT and variants of presentation as apical hypertrophic cardiomyopathy, allows identifying patients with high probability of sudden death. During the last few years, cardiac resonance and quantification of intramyocardial fibrosis (the basic mechanism of ventricular arrhythmias) have gained an important role in the evaluation of these patients.In particular, pediatric patients must have an individualized approach due to the poor prognosis at early ages and the uncertain role of different tools for risk assessment and treatment.

Predictors of risk for sudden death in childhood hypertrophic cardiomyopathy: the importance of the ECG risk score

ObjectiveTo establish which risk factors are predictive for sudden death in hypertrophic cardiomyopathy (HCM) diagnosed in childhood.MethodsA Swedish national cohort of patients with HCM diagnosed <19 years of age was...

Troponin as ischemic biomarker is related with all three echocardiographic risk factors for sudden death in hypertrophic cardiomyopathy (ESC Guidelines 2014)

BackgroundSudden cardiac death (SCD) risk stratification is the most important preventive action in patients with hypertrophic cardiomyopathy (HCM). The identification of the ischemia biomarker high sensitive troponin I (hs-TnI) role for this arrhythmic disease may provide additional information for SCD risk stratification. The aim of the study was to compare echocardiographic parameters (prognostic for risk stratification of SCD in HCM) among two subgroups of HCM patients: with elevated hs-TnI versus non-elevated hs-TnI level.MethodsIn 51 HCM patients (mean age 39 ± 8 years, 31 males and 20 females) an echocardiographic examination, including the stimulating maneuvers to provoke maximized LVOT gradient, was performed. The hs-TnI was measured 24 h later.ResultsBy comparing two subgroups of patients, 26 members with hs-TnI positive versus 25 with hs-TnI negative, the study showed that the values of all three parameters were greater: provocable left ventricular outflow tract gradient (LVOTG) – 49.1 ± 45.9 vs 25.5 ± 24.8 mmHg, p = 0.019; left atrial diameter – 50.1 ± 9.6 vs 43.9 ± 9.8 mmHg, p = 0.041; maximal LV thickness – 22.1 ± 5.3 vs 19.9 ± 34 mm, p = 0.029.ConclusionThe increased value of all three echocardiographic parameters used as risk factors for SCD (ESC Guidelines) is related to the elevated level of hs-TnI in HCM. Due to the high LVOTG – great hs-TnI relationship, exercise stress, both diagnostic and even rehabilitation/training, should be monitored by biomarker control.

P1597QT rate dependence in risk stratification for sudden death in hypertrophic cardiomyopathy

P1597QT rate dependence in risk stratification for sudden death in hypertrophic cardiomyopathy

Predicting risk of sudden death in hypertrophic cardiomyopathy: Can additional simple markers help?

Predicting risk of sudden death in hypertrophic cardiomyopathy: Can additional simple markers help?

Predicting risk of sudden death in hypertrophic cardiomyopathy: Can additional simple markers help?

Predicting risk of sudden death in hypertrophic cardiomyopathy: Can additional simple markers help?

THE RELATIONSHIP BETWEEN THE QUANTITATIVE EXTENT OF MYOCARDIAL FIBROSIS AND BURDEN OF NON-SUSTAINED VENTRICULAR TACHYCARDIA IN HYPERTROPHIC CARDIOMYOPATHY: A DELAYED CONTRAST ENHANCED MRI STUDY

Background: Non-sustained ventricular tachycardia (NSVT) has been shown to be independently associated with sudden death in hypertrophic cardiomyopathy (HCM). Previous studies have found late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) to be independently associated with the

Complete Heart Block in Hypertrophic Cardiomyopathy: A Rare Association.

Ventricular tachyarrhythmias are common in hypertrophic cardiomyopathy that may lead to syncope and sudden death. Bradyarrhythmia such as atrioventricular conduction disturbance, a relatively rare complication associated with hypertrophic cardiomyopathy, may also cause syncope and sudden death in hypertrophic cardiomyopathy. We report a 28-year old man who was diagnosed as a case of hypertrophic cardiomyopathy presented with syncope and complete heart block. Subsequently, a permanent pacemaker was implanted to the patient.

Prevention of sudden death in hypertrophic cardiomyopathy: bridging the gaps in knowledge.

Sudden cardiac death (SCD) is the most devastating complication of hypertrophic cardiomyopathy (HCM). Although the annual rate of SCD in the general HCM population is <1% per year according to contemporary series, there is still a small subset of patients who are at increased risk of SCD. The greatest challenge in the management of HCM is identifying those at increased risk as an implantable cardioverter defibrillator is a potentially life-saving therapy. In this review, we sought to summarize the available data on SCD in HCM and provide a clinical perspective on the current differing and somewhat conflicting European and American recommendations on risk stratification, with balanced guidance with regards to rational clinical decision making. Additionally, we sought to learn more on the actual implementation of the guidelines by HCM experts worldwide.

Historical perspectives on the implantable cardioverter-defibrillator and prevention of sudden death in hypertrophic cardiomyopathy.

The implantable cardioverter-defibrillator (ICD) was not originally envisioned as a treatment to prevent sudden death (SD) in young people with genetic heart diseases. In the case of hypertrophic cardiomyopathy (HCM), initially it was not known whether the ICD would be effective in patients with a disease very different morphologically and functionally from coronary artery disease. Nevertheless, several observational clinical studies have shown that the ICD reliably terminates life-threatening ventricular tachyarrhythmias in HCM, and is largely responsible for reducing HCM mortality to 0.5% per year, by preventing SD and changing the natural course of the disease.

The Importance of Genetic Testing in a Case of Sudden Death in Hypertrophic Cardiomyopathy due to Troponin I Mutation

Sudden death due to hypertrophic cardiomyopathy (HCM) is uncommon. Most cases of HCM are due to mutations in sarcomeric proteins. Mutations of the cardiac troponin I gene TNNI3 are rare. Over 15 mutations of the TNNI3 gene have been identified; the clinical, imaging and pathologic findings within the small subcategory are very diverse. While asymptomatic patients do not generally receive therapy, the entire group may be at risk of sudden death. Thus, affected individuals and their family members may require heightened surveillance. As such, accurate diagnosis at postmortem examination is important as it may have a direct impact on the health and well-being of surviving family members. We present the case of a 36-year-old man who collapsed and died while jogging. His sister had been recently diagnosed with hypertrophic cardiomyopathy. Consequently, the decedent had undergone transthoracic echocardiography that demonstrated only mild features suggestive of hypertrophic cardiomyopathy including non-obstructive asymmetric septal wall thickening of less than 30 mm in the absence of systolic anterior motion of the mitral valve or cardiomegaly. The autopsy confirmed the presence of mild septal hypertrophy (maximum 23 mm thickness) in the absence of cardiomegaly. Histologic features were typical of hypertrophic cardiomyopathy including septal myofiber disarray and nuclear enlargement. Mutational analysis of frozen myocardium demonstrated an Arg162Gln substitution in the cardiac troponin I gene (TNNI3) involving exon 7. This case highlights the importance of molecular/genetic analysis in the setting of sudden natural death, from both diagnostic and public health perspectives.

Genomic Testing and Genomic Care: Are They Talking to Each Other?

The principle of basing medical decisions on the concept of risk is not new. Table 1 shows comparative information on medical management guidance in a number of relatively common scenarios such as the use of statins in hypercholesterolaemia, treatment of hypertension, prevention of sudden death in hypertrophic cardiomyopathy, prevention of berry aneurysm rupture in autosomal dominant polycystic kidney disease, screening for Down Syndrome in pregnancy and the management of familial breast cancer susceptibility (Table 1).

Exercise Echocardiography in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a relatively frequent genetic disease that affects 1/500 human beings. Main problems with this disease are the development of symptoms in 10-20% of affected individuals, and the increased risk of sudden cardiac death (SCD) in a subset of patients with the disease. It is important to clarify the cause of symptoms and to assess the risk of sudden death in HCM because we do have therapies to relief these problems.

Perspectives on sudden death prevention in hypertrophic cardiomyopathy.

Sudden death (SD) is the most dramatic event in hypertrophic cardiomyopathy (HCM), often representing the first clinical manifestation of the disease, and the first concern of the clinicians who take care of such patients. HCM is now recognized as the primary cause of SD in young persons (<35 years of age), including trained athletes. Current data in unselected HCM patient populations report an approximate 0.7% per year incidence of SD, with the total cardiovascular mortality being around 1.4% annually. This review, incorporating contemporary research findings, addresses the major aspects of SD and its prevention in HCM. The traditional risk factors and other controversial risk factors for SD or the arbitrators for that event are thoroughly analyzed and the need for the development of a unique and accurate factor for SD risk stratification is discussed. Rather than enumerating clinical studies and guidelines, challenging problems concerning all aspects of SD in HCM, are critically appraised, highlighting current speculations and recommending future directions.

ECG risk score: A powerful predictor of sudden death in hypertrophic cardiomyopathy - genotype correlates

Background: An ECG risk score, scoring amplitudes and morphological abnormalities, which predicts a very high relative risk of sudden death if the point score is >5 has been described. The genotype-phenotype relationships, and correlation with sudden death have been studied in a geographical cohort of patients diagnosed with HCM < 19 yrs of age in the West Götaland Region, Sweden. Methods: Diagnosis was established with echocardiography, and ECG risk score was quantified from a 12-lead ECG according to Eur.Heart J 2010;31:439. DNA was analysed at international commercial laboratories. Results: 67 patients had ECG and echocardiographic data, 64% male. 45 (67%) had familial disease, and 12 Noonan-spectrum dysmorphology. Based on ECG-risk score 28 patients were high-risk (>5 points), and 39 low-risk (<6 points). The risk score correlated with death (correlation coefficient 0.57, p < 0.0001); there were 7 sudden deaths in the high-risk group and none in the low risk group (p = 0.0005). Familial disease was more common in the low-risk (85%) than in the high-risk group (37%), but a higher proportion of genotyped individuals had positive findings in the high-risk (81%) than in the low-risk group (67%). MYH7 mutations were more common than MYBPC3 (29% versus 19%) in the high-risk group, whereas in the low-risk group MYBPC was predominant (33%). Additional genes affected in the high-risk group were ACTC, MYL, MYPN, LAMP2, RAF 1 and PTNP11. Conclusions: The simple inexpensive ECG risk score effectively pinpoints high-risk individuals who require urgent full risk assessment, and where the yield of genetic testing is particularly high.