scholarly journals Mechanisms of Arrhythmogenicity of Hypertrophic Cardiomyopathy-Associated Troponin T (TNNT2) Variant I79N

2021 ◽  
Vol 9 ◽  
Author(s):  
Sanam Shafaattalab ◽  
Alison Y Li ◽  
Marvin G Gunawan ◽  
BaRun Kim ◽  
Farah Jayousi ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Hypertrophic Cardiomyopathy ◽  
Action Potential ◽  
Natriuretic Peptide ◽  
Troponin T ◽  
Sudden Cardiac Arrest ◽  
Human Action ◽  
Significant Shift ◽  
Ecm Remodeling ◽  
Increased Risk

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease and often results in cardiac remodeling and an increased incidence of sudden cardiac arrest (SCA) and death, especially in youth and young adults. Among thousands of different variants found in HCM patients, variants of TNNT2 (cardiac troponin T—TNNT2) are linked to increased risk of ventricular arrhythmogenesis and sudden death despite causing little to no cardiac hypertrophy. Therefore, studying the effect of TNNT2 variants on cardiac propensity for arrhythmogenesis can pave the way for characterizing HCM in susceptible patients before sudden cardiac arrest occurs. In this study, a TNNT2 variant, I79N, was generated in human cardiac recombinant/reconstituted thin filaments (hcRTF) to investigate the effect of the mutation on myofilament Ca2+ sensitivity and Ca2+ dissociation rate using steady-state and stopped-flow fluorescence techniques. The results revealed that the I79N variant significantly increases myofilament Ca2+ sensitivity and decreases the Ca2+ off-rate constant (koff). To investigate further, a heterozygous I79N+/−TNNT2 variant was introduced into human-induced pluripotent stem cells using CRISPR/Cas9 and subsequently differentiated into ventricular cardiomyocytes (hiPSC-CMs). To study the arrhythmogenic properties, monolayers of I79N+/− hiPSC-CMs were studied in comparison to their isogenic controls. Arrhythmogenesis was investigated by measuring voltage (Vm) and cytosolic Ca2+ transients over a range of stimulation frequencies. An increasing stimulation frequency was applied to the cells, from 55 to 75 bpm. The results of this protocol showed that the TnT-I79N cells had reduced intracellular Ca2+ transients due to the enhanced cytosolic Ca2+ buffering. These changes in Ca2+ handling resulted in beat-to-beat instability and triangulation of the cardiac action potential, which are predictors of arrhythmia risk. While wild-type (WT) hiPSC-CMs were accurately entrained to frequencies of at least 150 bpm, the I79N hiPSC-CMs demonstrated clear patterns of alternans for both Vm and Ca2+ transients at frequencies >75 bpm. Lastly, a transcriptomic analysis was conducted on WT vs. I79N+/−TNNT2 hiPSC-CMs using a custom NanoString codeset. The results showed a significant upregulation of NPPA (atrial natriuretic peptide), NPPB (brain natriuretic peptide), Notch signaling pathway components, and other extracellular matrix (ECM) remodeling components in I79N+/− vs. the isogenic control. This significant shift demonstrates that this missense in the TNNT2 transcript likely causes a biophysical trigger, which initiates this significant alteration in the transcriptome. This TnT-I79N hiPSC-CM model not only reproduces key cellular features of HCM-linked mutations but also suggests that this variant causes uncharted pro-arrhythmic changes to the human action potential and gene expression.

scholarly journals J wave is associated with increased risk of sudden cardiac arrest in patients with hypertrophic cardiomyopathy

2013 ◽  
Vol 41 (4) ◽  
pp. 1281-1290 ◽  
Author(s):  
Yanbing Li ◽  
Jun Mao ◽  
Qian Yan ◽  
Shuyuan Qi ◽  
Xiaoyan Liu ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Hypertrophic Cardiomyopathy ◽  
Sudden Cardiac Arrest ◽  
Increased Risk ◽  
J Wave

scholarly journals N-Terminal Pro-B-Type Natriuretic Peptide as a Prognostic Indicator for 30-Day Mortality Following Out-of-Hospital Cardiac Arrest: A prospective observational study.

2020 ◽  
Author(s):  
Reidun Aarsetøy ◽  
Torbjørn Omland ◽  
Helge Røsjø ◽  
Heidi Strand ◽  
Thomas Werner Lindner ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Natriuretic Peptide ◽  
Troponin T ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Sudden Cardiac Arrest ◽  
Cardiac Biomarkers ◽  
Prognostic Information ◽  
Clinical Trial Registration ◽  
Hospital Cardiac Arrest

Abstract Background: Early risk stratification applying cardiac biomarkers may prove useful in sudden cardiac arrest patients. We investigated the prognostic utility of early-on levels of high sensitivity cardiac troponin-T (hs-cTnT), copeptin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with out-of-hospital cardiac arrest (OHCA).Methods: We conducted a prospective observational unicenter study, including patients with OHCA of assumed cardiac origin from the Southwestern part of Norway from 2007 until 2010. Blood samples for later measurements were drawn during cardiopulmonary resuscitation or at hospital admission. Results: A total of 114 patients were included, 37 patients with asystole and 77 patients with VF as first recorded heart rhythm. Forty-four patients (38.6%) survived 30-day follow-up. Neither hs-cTnT (p = 0.49), nor copeptin (p = 0.39) differed between non-survivors and survivors, whereas NT-proBNP was higher in non-survivors and significantly associated with time to death, with a hazard ratio (HR) for patients in the highest compared to the lowest quartile of 4.6 (95% CI 2.1 – 10.1), p < 0.001. This association was attenuated in the multivariable analysis [HR 2.18 (95% CI 0.83 – 5.72)], p = 0.11. NT-proBNP was significantly higher in asystole- as compared to VF-patients, p < 0.001.Conclusions: In OHCA, NT-proBNP was significantly associated with 30-day survival in univariate analysis, but associations were attenuated after multivariable adjustment. Hs-cTnT and copeptin did not provide prognostic information following OHCA.Clinical Trial Registration: ClinicalTrials. gov, NCT02886273.

Clinical outcomes in adult athletes with hypertrophic cardiomyopathy: a 7-year follow-up study

2020 ◽  
Vol 54 (16) ◽  
pp. 1008-1012 ◽  
Author(s):  
Antonio Pelliccia ◽  
Stefano Caselli ◽  
Matteo Pelliccia ◽  
Maria Beatrice Musumeci ◽  
Erika Lemme ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Hypertrophic Cardiomyopathy ◽  
Sport Participation ◽  
Sudden Cardiac Arrest ◽  
Left Ventricular ◽  
Rank Test ◽  
Competitive Sport ◽  
Increased Risk ◽  
Exercise Programmes

ObjectiveCurrent guidelines recommend precautionary disqualification from competitive sports in patients with hypertrophic cardiomyopathy (HCM). We assessed the incidence of cardiovascular events in a cohort of patients with HCM engaged in long-term exercise programmes and competitive sport.MethodsWe reviewed data on 88 consecutive athletes diagnosed with HCM, from 1997 to 2017; 92% male, 98% Caucasian, median age 31 (IQR: 19–44) years. All participated in regular exercise programmes and competitive sport at study entry.We performed follow-up evaluation after 7±5 (1–21) years. 61 (69%) of the athletes had substantially reduced or stopped exercise and sport (ie, HCM-detrained), and 27 had continued with regular training and sport competitions (HCM-trained). At baseline evaluation, both groups were similar for age, gender balance, symptoms, ECG abnormalities, extent of left ventricular hypertrophy, arrhythmias and risk profile for sudden cardiac death/arrest.ResultsDuring the follow-up period, two participants suffered sudden cardiac arrest or death (0.3% per year) both outside of sport participation. In addition, 19 (22%) reported symptoms (syncope in 3, palpitations in 10, chest pain in 4 and dyspnoea in 2). The Kaplan-Meier analyses of freedom from combined sudden cardiac arrest/death and symptoms (log-rank test p=0.264) showed no differences between HCM-trained and detrained patients.ConclusionIn this adult cohort of low-risk HCM athletes, voluntary decision to pursue in participation in competitive sport events was not associated with increased risk for major cardiac events or clinical worsening compared with decision to reduce or withdraw from exercise programmes and sport. Similar results may not be seen in younger or racially diverse athlete populations, or in patients with more severe HCM phenotypes.

scholarly journals N-Terminal Pro-B-Type Natriuretic Peptide as a Prognostic Indicator for 30-Day Mortality Following Out-of-Hospital Cardiac Arrest: A prospective observational study.

2020 ◽  
Author(s):  
Reidun Aarsetøy ◽  
Torbjørn Omland ◽  
Helge Røsjø ◽  
Heidi Strand ◽  
Thomas Werner Lindner ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Natriuretic Peptide ◽  
Troponin T ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Sudden Cardiac Arrest ◽  
Cardiac Biomarkers ◽  
Prognostic Information ◽  
Clinical Trial Registration ◽  
Hospital Cardiac Arrest

Abstract Background: Early risk stratification applying cardiac biomarkers may prove useful in sudden cardiac arrest patients. We investigated the prognostic utility of early-on levels of high sensitivity cardiac troponin-T (hs-cTnT), copeptin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with out-of-hospital cardiac arrest (OHCA).Methods: We conducted a prospective observational unicenter study, including patients with OHCA of assumed cardiac origin from the southwestern part of Norway from 2007 until 2010. Blood samples for later measurements were drawn during cardiopulmonary resuscitation or at hospital admission.Results: A total of 114 patients were included, 37 patients with asystole and 77 patients with VF as first recorded heart rhythm. Forty-four patients (38.6 %) survived 30-day follow-up. Neither hs-cTnT (p = 0.49), nor copeptin (p = 0.39) differed between non-survivors and survivors, whereas NT-proBNP was higher in non-survivors (p < 0.001) and significantly associated with 30-days all-cause mortality in univariate analysis, with a hazard ratio (HR) for patients in the highest compared to the lowest quartile of 4.6 (95% confidence interval (CI), 2.1 – 10.1), p < 0.001. This association was no longer significant in multivariable analysis applying continuous values, [HR 0.96, (95% CI, 0.64 - 1.43), p = 0.84]. Similar results were obtained by dividing the population by survival at hospital admission, excluding non-ROSC patients on-scene [HR 0.93 (95% CI, 0.50 - 1.73), P = 0.83]. We also noted that NT-proBNP was significantly higher in asystole- as compared to VF-patients, p < 0.001.Conclusions: Early-on levels of hs-cTnT, copeptin and NT-proBNP did not provide independent prognostic information following OHCA. Prediction was unaffected by excluding on-scene non-ROSC patients in the multivariable analysis. Clinical Trial Registration: ClinicalTrials. gov, NCT02886273.

scholarly journals N-Terminal Pro-B-Type Natriuretic Peptide as a Prognostic Indicator for 30-Day Mortality Following Out-of-Hospital Cardiac Arrest: A prospective observational study

2020 ◽  
Author(s):  
Reidun Aarsetøy ◽  
Torbjørn Omland ◽  
Helge Røsjø ◽  
Heidi Strand ◽  
Thomas Werner Lindner ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Natriuretic Peptide ◽  
Troponin T ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Sudden Cardiac Arrest ◽  
Cardiac Biomarkers ◽  
Prognostic Information ◽  
Clinical Trial Registration ◽  
Hospital Cardiac Arrest

Abstract Background Early risk stratification applying cardiac biomarkers may prove useful in sudden cardiac arrest patients. We investigated the prognostic utility of early-on levels of high sensitivity cardiac troponin-T (hs-cTnT), copeptin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with out-of-hospital cardiac arrest (OHCA). Methods We conducted a prospective observational unicenter study, including patients with OHCA of assumed cardiac origin from the southwestern part of Norway from 2007 until 2010. Blood samples for later measurements were drawn during cardiopulmonary resuscitation or at hospital admission. Results A total of 114 patients were included, 37 patients with asystole and 77 patients with VF as first recorded heart rhythm. Forty-four patients (38.6%) survived 30-day follow-up. Neither hs-cTnT (p = 0.49), nor copeptin (p = 0.39) differed between non-survivors and survivors, whereas NT-proBNP was higher in non-survivors and significantly associated with time to death, with a hazard ratio (HR) for patients in the highest compared to the lowest quartile of 4.6 (95% CI 2.1–10.1), p < 0.001. This association was attenuated in the multivariable analysis [HR 2.18 (95% CI 0.83–5.72)], p = 0.11. NT-proBNP was significantly higher in asystole- as compared to VF-patients, p < 0.001. Conclusions In OHCA, NT-proBNP was significantly associated with 30-day survival in univariate analysis, but associations were attenuated after multivariable adjustment. Hs-cTnT and copeptin did not provide prognostic information following OHCA. Clinical Trial Registration: ClinicalTrials. gov, NCT02886273.

scholarly journals Discovery of predictors of sudden cardiac arrest in diabetes: rationale and outline of the RESCUED (REcognition of Sudden Cardiac arrest vUlnErability in Diabetes) project

Open Heart ◽  
2021 ◽  
Vol 8 (1) ◽  
pp. e001554
Author(s):  
Laura H van Dongen ◽  
Peter P Harms ◽  
Mark Hoogendoorn ◽  
Dominic S Zimmerman ◽  
Elisabeth M Lodder ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Prognostic Model ◽  
Early Recognition ◽  
Sudden Cardiac Arrest ◽  
Clinical Genetic ◽  
Innovative Strategy ◽  
Rare Variant Analysis ◽  
Increased Risk ◽  
Gp Care

IntroductionEarly recognition of individuals with increased risk of sudden cardiac arrest (SCA) remains challenging. SCA research so far has used data from cardiologist care, but missed most SCA victims, since they were only in general practitioner (GP) care prior to SCA. Studying individuals with type 2 diabetes (T2D) in GP care may help solve this problem, as they have increased risk for SCA, and rich clinical datasets, since they regularly visit their GP for check-up measurements. This information can be further enriched with extensive genetic and metabolic information.AimTo describe the study protocol of the REcognition of Sudden Cardiac arrest vUlnErability in Diabetes (RESCUED) project, which aims at identifying clinical, genetic and metabolic factors contributing to SCA risk in individuals with T2D, and to develop a prognostic model for the risk of SCA.MethodsThe RESCUED project combines data from dedicated SCA and T2D cohorts, and GP data, from the same region in the Netherlands. Clinical data, genetic data (common and rare variant analysis) and metabolic data (metabolomics) will be analysed (using classical analysis techniques and machine learning methods) and combined into a prognostic model for risk of SCA.ConclusionThe RESCUED project is designed to increase our ability at early recognition of elevated SCA risk through an innovative strategy of focusing on GP data and a multidimensional methodology including clinical, genetic and metabolic analyses.

N-terminal pro-brain natriuretic peptide and sudden cardiac death in hypertrophic cardiomyopathy

Heart ◽  
2020 ◽  
pp. heartjnl-2020-317701
Author(s):  
Guixin Wu ◽  
Jie Liu ◽  
Shuiyun Wang ◽  
Shiqin Yu ◽  
Ce Zhang ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Sudden Cardiac Death ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Cardiac Death ◽  
Cardiac Fibrosis ◽  
Discrimination Performance ◽  
Net Reclassification Improvement ◽  
C Statistic ◽  
Increased Risk

ObjectiveElevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are associated with heart failure-related death in hypertrophic cardiomyopathy (HCM), but the relationship between NT-proBNP level and sudden cardiac death (SCD) in HCM remains undefined.MethodsThe study prospectively enrolled 977 unrelated patients with HCM with available NT-proBNP results who were prospectively enrolled and followed for 3.0±2.1 years. The Harrell’s C-statistic under the receiver operating characteristic curve was calculated to evaluate discrimination performance. A combination model was constructed by adding NT-proBNP tertiles to the HCM Risk-SCD model. The correlation between log NT-proBNP level and cardiac fibrosis as measured by late gadolinium enhancement (LGE) or Masson’s staining was analysed.ResultsDuring follow-up, 29 patients had SCD. Increased log NT-proBNP levels were associated with an increased risk of SCD events (adjusted HR 22.27, 95% CI 10.93 to 65.63, p<0.001). The C-statistic of NT-proBNP in predicting SCD events was 0.80 (p<0.001). The combined model significantly improved the predictive efficiency of the HCM Risk-SCD model from 0.72 to 0.81 (p<0.05), with a relative integrated discrimination improvement of 0.002 (p<0.001) and net reclassification improvement of 0.67 (p<0.001). Furthermore, log NT-proBNP levels were significantly correlated with cardiac fibrosis as detected either by LGE (r=0.257, p<0.001) or by Masson’s trichrome staining in the myocardium (r=0.198, p<0.05).ConclusionNT-proBNP is an independent predictor of SCD in patients with HCM and may help with risk stratification of this disease.

Sudden cardiac arrest in 15-year-old girl. Could it be avoided?

2018 ◽  
Vol 1 (46) ◽  
pp. 43-48
Author(s):  
Maria Posadowska ◽  
Maria Miszczak-Knecht ◽  
Alicja Mirecka-Rola ◽  
Katarzyna Bieganowska
Keyword(s):  
Cardiac Arrest ◽  
Hypertrophic Cardiomyopathy ◽  
Cardiac Death ◽  
Sudden Cardiac Arrest ◽  
Postmortem Examination ◽  
Cardiac Care ◽  
Related Family ◽  
Asymptomatic Patients ◽  
History Of ◽  
Genetically Determined

We present a case of a 15-year-old girl after sudden cardiac arrest because of ventricular fibrillation. Hypertrophic cardiomyopathy was diagnosed. Family history of patient was positive – her uncle (mother’s brother) died suddenly at the age of 21, postmortem examination showed hypertrophic cardiomyopathy. The deceased man’s family was not under cardiac care. The presented case proves, that due to genetically determined cardiac diseases such as cardiomyopathies and channelopathies, all related family members should be examined cardiologically. Diagnosis of the disease in asymptomatic patients would allow the implementation of treatment and reduce the risk of a sudden cardiac arrest / sudden cardiac death.

scholarly journals Prognostic Value of N-Terminal Pro-Brain Natriuretic Peptide and High-Sensitivity Troponin T Levels in the Natural History of Transthyretin Amyloid Cardiomyopathy and Their Evolution after Tafamidis Treatment

2021 ◽  
Vol 10 (21) ◽  
pp. 4868
Author(s):  
Silvia Oghina ◽  
Constant Josse ◽  
Mélanie Bézard ◽  
Mounira Kharoubi ◽  
Marc-Antoine Delbarre ◽  
...  
Keyword(s):  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Prognostic Value ◽  
Troponin T ◽  
High Sensitivity ◽  
Relative Increase ◽  
High Sensitivity Troponin ◽  
Increased Risk ◽  
Amyloid Cardiomyopathy ◽  
High Sensitivity Troponin T

Background: We assesse the evolution and prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (cTnT-HS) in transthyretin amyloid cardiomyopathy (ATTR-CA) before and after tafamidis treatment. Methods and Results: 454 ATTR-CA patients without tafamidis (Cohort A) and 248 ATTR-CA with tafamidis (Cohort B) were enrolled. Event-free survival (EFS) events were death, heart transplant, or acute heart failure. In Cohort A, 27% of patients maintained NT-proBNP < 3000 ng/L and 14% cTnT-HS < 50 ng/L at 12 months relative to baseline levels. In Cohort B, the proportions were 49% and 29%, respectively. In Cohort A, among the 333 patients without an increased NT-proBNP > 50% relative to baseline EFS was extended compared to the 121 patients with an increased NT-proBNP > 50% (HR: 0.75 [0.57; 0.98]; p = 0.032). In Cohort A, baseline NT-proBNP > 3000 ng/L and cTnT-HS > 50 ng/L and a relative increase of NT-proBNP > 50% during follow-up were independent prognostic factors of EFS. The slopes of logs NT-proBNP and cTnT-HS increased with time before and stabilized after tafamidis. Conclusion: ATTR-CA patients with increasing NT-proBNP had an increased risk of EFS. Tafamidis stabilize NT-proBNP and cTnT-HS increasing, even if initial NT-proBNP levels were >3000 ng/L. Thus suggesting that all patients, irrespective of baseline NT-proBNP levels, may benefit from tafamidis.

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