Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Introduction We recently optimized our ECG imaging (ECGi) method for the estimation of endo- and epicardial activation during sinus rhythm. In patients with arrhythmogenic cardiomyopathy, late gadolinium enhancement (LGE)-CMR can identify regional myocardial injury and the combination of structural and electrical information may provide valuable insight in disease progression and risk stratification. However, the effect of structural disease and local conduction delay on the ECGi estimation of ventricular activation has not been studied. Purpose Evaluate the relation between LGE-CMR and non-invasively estimated local conduction velocity (CV). Methods 8 pathogenic mutation carriers (PKP2/PLN) underwent LGE-CMR for clinical follow up and 67 lead body surface mapping. Subject specific triangulated surface heart/torso/lung meshes were created. ECGi activation sequences were used to determine local CV with the triangulation method. The LGE location was identified according to the AHA 17 segment model. Per segment, variation in CV was computed and local activation timing maps and CV maps were constructed. Results Isochronal crowding was observed in subjects in segments with LGE (figure, red boxes) and locally, conduction velocity decreased. Variation in conduction velocity per segment in subjects with extensive LGE presence (>9 segments) was higher 0.031±0.018 vs. 0.026±0.013 m/s/cm2 in subjects without. Conclusion Our preliminary results indicate the ability of the ECGi method to identify regions with higher variation in local CV. This increase in CV variability might be used to assess the vulnerability to cardiac arrhythmia. Analysis will be extended towards the RV and subsequently, more subjects will be included.
Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Netherlands Cardio Vascular Research Initiative (CVON): the Dutch heart foundation Background Mutations in phospholamban (PLN, most often PLNR14Del), a protein that regulates Ca2+ homeostasis in cardiomyocytes, are found in patients diagnosed with arrhythmogenic (ACM) and dilated cardiomyopathy (DCM). Fibrosis formation in the heart is one of the hallmarks in PLN patients, which compromises cardiac contractility and predisposes to arrhythmogenicity. Collagen type I is the most abundant type of collagen in the heart (85%). During continuous collagen synthesis propeptides, like procollagen type I carboxy-terminal propeptide (PICP) and during collagen breakdown, C-terminal telopeptide collagen type I (ICTP), are released into the circulation. Clinically, detection of fibrosis occurs via echo or MRI, however difficulties arise when patchy fibrosis has to be detected. Purpose To investigate if PICP and ICTP levels in blood are useful predictive biomarkers for clinical outcome in PLN patients. Methods 78 serum and EDTA blood samples were collected on the same day from ACM diagnosed (n = 12), DCM diagnosed (n = 14) or non-classified (n = 52) PLN patients. PICP levels were measured with an ELISA assay and ICTP with a RIA. Clinical data were subtracted two years around blood collection from Redcap, a Dutch database with medical records from PLN patients. Data were not normally distributed, so Spearman’s correlation coefficient and Mann-Whitney test were used. Results Gender, age and PICP/ICTP ratios were similarly distributed between the subgroups. First, we checked if clinical data subtracted two years around blood collection provided reliable results regarding clinical outcome. Patients who underwent clinical testing 5.5 weeks around blood collection revealed that clinical data were in line with the best-fitted line of the linear regression and therefore provide reliable results. Next, the potential correlation of fibrosis biomarkers with electrical parameters was assessed. Increased PICP/ICTP ratios suggest a higher collagen deposition. Although there was no correlation with prolonged QRS duration (Rs 0.13, n = 62, ns), subgroup analysis showed a significant weak correlation for non-classified patients (Rs 0.32, n = 38, p = 0.05). No significant correlation was found for ACM or DCM patients; however, groups were rather small. PICP/ICTP ratio was significantly higher in patients with T wave inversion and premature ventricular contractions (PVCs) during an exercise tolerance test. A weak inverted correlation was found with left ventricular ejection fraction and PICP/ICTP (Rs -0.28, n = 23, ns), while moderate correlations between the ratio and end diastolic volume, and end systolic volume exist (both Rs 0.40, n = 23, p = 0.06). Conclusion High PICP/ICTP ratios correlate with clinical outcome in PLN patients, such as T wave inversion and PVCs. However, the size and heterogeneity of the patient group resulted in weak to moderate correlation coefficients and might therefore currently precludes to use PICP and ICTP levels as biomarker.
Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NWO - ZonMw (VIDI grant 016.176.340 to JL) Dutch Heart Foundation (ERA-CVD JTC2018 grant 2018T094; Dr. Dekker Program grant 2015T082 to JL) The Netherlands Cardio Vascular Research Initiative (CVON): the Dutch Heart Foundation, Dutch Federation of University Medical Center, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences (CVON-eDETECT 2015-12 and CVON-PREDICT2 2018-30 to TvV). Background Patients with arrhythmogenic cardiomyopathy (ACM), an inherited progressive cardiac disease, mostly remain asymptomatic until the occurrence of life-threatening arrhythmias. Previous research identified disturbed calcium handling as a potential disease-initiating mechanism [1], but how this translates to arrhythmogenesis and cardiac mechanical dysfunction remains unknown. Purpose To characterize disturbed molecular regulators of intracellular calcium (Ca2+) handling in patients with ACM and predict their effects on action potential (AP), calcium transient (CaT) and tension development in both left and right ventricles (LV, RV) using a computer model of cellular electromechanics. Methods We performed gene expression (qPCR) and protein level (Western blot) analysis using LV and RV tissue samples obtained from 5 ACM patients who underwent heart transplant and 5 controls with no history of cardiac disease. Changes in protein levels were implemented in our recent human electromechanical cardiomyocyte computer model [2]. CaT, AP and tension traces were simulated and compared to control. Clinical data (age, sex, genetics, ECG, echocardiography) were related to the simulation outcome. Results Measured protein levels varied significantly between the 5 patients and between individual LV and RV samples. Exemplary results for one ACM patient are shown in the figure below. In the LV, AP duration was shorter than control (221ms vs. 255ms), CaT peak was increased (0.52µM vs. 0.39µM) but CaT amplitude was reduced due to increased diastolic Ca2+ (0.26µM vs. 0.060µM). Relaxation was also impaired, as shown by a longer CaT and tension duration (965ms vs. 640ms), and an increased diastolic tension (10mN vs. 4.8mN). In the RV, AP duration was shortened, and CaT and tension peak were lower than in the LV (0.37µM and 13.6mN). Diastolic levels were elevated compared to control, and CaT and tension development were prolonged. This can be related to the measured Ca2+ changes: in the LV, a lower activity of the sodium-calcium exchanger (NCX) (22% of control) and SERCA pump (52%) combined with an increased ryanodine receptor (RyR) activity (96%) may impair the extrusion of Ca2+, leading to accumulation of Ca2+ and increased diastolic Ca2+ levels. In the RV, milder changes in NCX (48% of control) and RyR (11%) may explain the larger Ca2+ extrusion, leading to lower CaT peak and diastolic levels. The patient showed a normal LV size, a severely dilated RV, as well as a poor LV fractional shortening suggesting increased ventricular stiffness, in line with the potential impaired relaxation shown by the simulations. Conclusion By integrating protein level data from ACM patients into a computational model of cellular electromechanics, we quantified the electromechanical effects of patient-specific Ca2+ handling changes. Future whole-heart extensions of this work have the potential to identify and understand proarrhythmic mechanisms in ACM patients.
Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NWO - ZonMw (VIDI grant 016.176.340 to JL) Dutch Heart Foundation (ERA-CVD JTC2018 grant 2018T094; Dr. Dekker Program grant 2015T082 to JL) The Netherlands Cardio Vascular Research Initiative (CVON): the Dutch Heart Foundation, Dutch Federation of University Medical Center, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences (CVON-eDETECT 2015-12 and CVON-PREDICT2 2018-30 to TvV). Background Patients with arrhythmogenic cardiomyopathy (ACM), an inherited progressive cardiac disease, mostly remain asymptomatic until the occurrence of life-threatening arrhythmias. Previous research identified disturbed calcium handling as a potential disease-initiating mechanism [1], but how this translates to arrhythmogenesis and cardiac mechanical dysfunction remains unknown. Purpose To characterize disturbed molecular regulators of intracellular calcium (Ca2+) handling in patients with ACM and predict their effects on action potential (AP), calcium transient (CaT) and tension development in both left and right ventricles (LV, RV) using a computer model of cellular electromechanics. Methods We performed gene expression (qPCR) and protein level (Western blot) analysis using LV and RV tissue samples obtained from 5 ACM patients who underwent heart transplant and 5 controls with no history of cardiac disease. Changes in protein levels were implemented in our recent human electromechanical cardiomyocyte computer model [2]. CaT, AP and tension traces were simulated and compared to control. Clinical data (age, sex, genetics, ECG, echocardiography) were related to the simulation outcome. Results Measured protein levels varied significantly between the 5 patients and between individual LV and RV samples. Exemplary results for one ACM patient are shown in the figure below. In the LV, AP duration was shorter than control (221ms vs. 255ms), CaT peak was increased (0.52µM vs. 0.39µM) but CaT amplitude was reduced due to increased diastolic Ca2+ (0.26µM vs. 0.060µM). Relaxation was also impaired, as shown by a longer CaT and tension duration (965ms vs. 640ms), and an increased diastolic tension (10mN vs. 4.8mN). In the RV, AP duration was shortened, and CaT and tension peak were lower than in the LV (0.37µM and 13.6mN). Diastolic levels were elevated compared to control, and CaT and tension development were prolonged. This can be related to the measured Ca2+ changes: in the LV, a lower activity of the sodium-calcium exchanger (NCX) (22% of control) and SERCA pump (52%) combined with an increased ryanodine receptor (RyR) activity (96%) may impair the extrusion of Ca2+, leading to accumulation of Ca2+ and increased diastolic Ca2+ levels. In the RV, milder changes in NCX (48% of control) and RyR (11%) may explain the larger Ca2+ extrusion, leading to lower CaT peak and diastolic levels. The patient showed a normal LV size, a severely dilated RV, as well as a poor LV fractional shortening suggesting increased ventricular stiffness, in line with the potential impaired relaxation shown by the simulations. Conclusion By integrating protein level data from ACM patients into a computational model of cellular electromechanics, we quantified the electromechanical effects of patient-specific Ca2+ handling changes. Future whole-heart extensions of this work have the potential to identify and understand proarrhythmic mechanisms in ACM patients.
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