scholarly journals Identification of SCN5a p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease

2021 ◽  
Vol 22 (23) ◽  
pp. 12990
Author(s):  
Farbod Sedaghat-Hamedani ◽  
Sabine Rebs ◽  
Ibrahim El-Battrawy ◽  
Safak Chasan ◽  
Tobias Krause ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Xenopus Oocytes ◽  
Family Members ◽  
Large Family ◽  
Left Ventricular ◽  
Cardiac Conduction ◽  
Left Ventricular Ejection ◽  
Na Channel ◽  
Loss Of Function ◽  
Induced Pluripotent

Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional analyses. In this study, by investigating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we evaluated the pathogenicity of the p.C335R sodium voltage-gated channel alpha subunit 5 (SCN5a) variant in a large family with familial DCM and conduction disease. Methods: A four-generation family with autosomal dominant familial DCM was investigated. Next-generation sequencing (NGS) was performed in all 16 family members. Clinical deep phenotyping, including endomyocardial biopsy, was performed. Skin biopsies from two patients and one healthy family member were used to generate human-induced pluripotent stem cells (iPSCs), which were then differentiated into cardiomyocytes. Patch-clamp analysis with Xenopus oocytes and iPSC-CMs were performed. Results: A SCN5a variant (c.1003T>C; p.C335R) could be detected in all family members with DCM or conduction disease. A novel truncating TTN variant (p.Ser24998LysfsTer28) could also be identified in two family members with DCM. Family members with the SCN5a variant (p.C335R) showed significantly longer PQ and QRS intervals and lower left ventricular ejection fractions (LV-EF). All four patients who received CRT-D were non-responders. Electrophysiological analysis with Xenopus oocytes showed a loss of function in SCN5a p.C335R. Na+ channel currents were also reduced in iPSC-CMs from DCM patients. Furthermore, iPSC-CM with compound heterozygosity (SCN5a p.C335R and TTNtv) showed significant dysregulation of sarcomere structures, which may be contributed to the severity of the disease and earlier onset of DCM. Conclusion: The SCN5a p.C335R variant is causing a loss of function of peak INa in patients with DCM and cardiac conduction disease. The co-existence of genetic variants in channels and structural genes (e.g., SCN5a p.C335R and TTNtv) increases the severity of the DCM phenotype.

scholarly journals Familial dilated cardiomyopathy with RBM20 mutation in an Indian patient: a case report

2021 ◽  
Vol 73 (1) ◽  
Author(s):  
Soumi Das ◽  
Sandeep Seth
Keyword(s):  
Ejection Fraction ◽  
Dilated Cardiomyopathy ◽  
Age Of Onset ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Early Age ◽  
Indian Patient ◽  
Ventricular Ejection Fraction ◽  
First Case

Abstract Background Dilated cardiomyopathy (DCM) is a disease of the heart muscle characterized by ventricular dilation and a left ventricular ejection fraction of less than 40%. Unlike hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC), DCM-causing mutations are present in a large number of genes. In the present study, we report a case of the early age of onset of DCM associated with a pathogenic variant in the RBM20 gene in a patient from India. Case presentation A 19-year-old Indian male diagnosed with DCM was suggested for heart transplantation. His ECG showed LBBB and echocardiography showed an ejection fraction of 14%. He had a sudden cardiac death. A detailed family history revealed it to be a case of familial DCM. Genetic screening identified the c.1900C>T variant in the RBM20 gene which led to a missense variant of amino acid 634 (p.Arg634Trp). Conclusion To the best of our knowledge, the variant p.Arg634Trp has been earlier reported in the Western population, but this is the first case of p.Arg634Trp in an Indian patient. The variant has been reported to be pathogenic at an early age of onset; therefore, close clinical follow-up should be done for the family members caring for the variant.

scholarly journals Temporal trends in outcome and patient characteristics in dilated cardiomyopathy, data from the Swedish Heart Failure Registry 2003–2015

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Helen Sjöland ◽  
Jonas Silverdal ◽  
Entela Bollano ◽  
Aldina Pivodic ◽  
Ulf Dahlström ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Temporal Trends ◽  
Physical Symptoms ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Continuous Change ◽  
Ventricular Ejection Fraction ◽  
Increased Risk ◽  
Over Time

Abstract Background Temporal trends in clinical composition and outcome in dilated cardiomyopathy (DCM) are largely unknown, despite considerable advances in heart failure management. We set out to study clinical characteristics and prognosis over time in DCM in Sweden during 2003–2015. Methods DCM patients (n = 7873) from the Swedish Heart Failure Registry were divided into three calendar periods of inclusion, 2003–2007 (Period 1, n = 2029), 2008–2011 (Period 2, n = 3363), 2012–2015 (Period 3, n = 2481). The primary outcome was the composite of all-cause death, transplantation and hospitalization during 1 year after inclusion into the registry. Results Over the three calendar periods patients were older (p = 0.022), the proportion of females increased (mean 22.5%, 26.4%, 27.6%, p = 0.0001), left ventricular ejection fraction was higher (p = 0.0014), and symptoms by New York Heart Association less severe (p < 0.0001). Device (implantable cardioverter defibrillator and/or cardiac resynchronization) therapy increased by 30% over time (mean 11.6%, 12.3%, 15.1%, p < 0.0001). The event rates for mortality, and hospitalization were consistently decreasing over calendar periods (p < 0.0001 for all), whereas transplantation rate was stable. More advanced physical symptoms correlated with an increased risk of a composite outcome over time (p = 0.0043). Conclusions From 2003 until 2015, we observed declining mortality and hospitalizations in DCM, paralleled by a continuous change in both demographic profile and therapy in the DCM population in Sweden, towards a less affected phenotype.

Abstract 13785: Left Ventricular Contractile Entropy in 99mTc-Sestamibi SPECT is a Novel Prognostic Predictor in Patients with Non-ischemic Dilated Cardiomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Naoaki Kano ◽  
Takahiro Okumura ◽  
Akinori Sawamura ◽  
Naoki Watanabe ◽  
Hiroaki Mori ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Sampling Point ◽  
Cardiac Events ◽  
Ventricular Ejection Fraction ◽  
Qrs Duration ◽  
Non Ischemic Dilated Cardiomyopathy ◽  
The Mean ◽  
99Mtc Sestamibi

Background: It has been reported that mechanical dispersion of myocardial contraction is increased in failing myocardium. However little is known about the association between contractile entropy evaluated by myocardial scintigraphy and prognosis in patients with non-ischemic dilated cardiomyopathy (NIDCM). Purpose: We aimed to investigate the prognostic value of contractile entropy in patients with NIDCM. Methods: Forty-seven patients (38 male, 55.1 years) with NIDCM were performed gated 99mTc-sestamibi myocardial perfusion SPECT (GMPS) and endomyocardial biopsy. Entropy was automatically calculated as a result of contractile phase analysis for each myocardial sampling point from GMPS, and it reflects a dispersion of global mechanical contraction. All patients were allocated into two groups based on the median of entropy; HE-group: entropy≥0.61 and LE-group: entropy<0.61. All patients were followed up at the mean of 2.8 years. Results: The mean QRS duration, left ventricular ejection fraction (LVEF) and plasma brain natriuretic peptide (BNP) levels were 114 msec, 35% and 225 pg/mL, respectively. Although there were no significant differences in QRS duration and plasma BNP levels between the two groups, LVEF was lower in the HE-group than in the LE-group (31.1% vs 39.8%, p=0.002). In Kaplan-Meier survival analysis, cardiac event rate was significantly higher in the HE-group (Figure). Cox proportional hazard analysis revealed that the HE-group was a significant determinant of cardiac events (Hazard Ratio: 7.66; 95%CI: 0.070-2.532; p=0.033). The mRNA expression level of sarcoplasmic endoplasmic reticulum Ca2+ ATPase (SERCA2a) in biopsy specimens was significantly lower in the LE-group (p=0.015). Conclusion: Contractile entropy, reflecting an impairment of global left ventricular contraction, might be useful to predict a poor prognosis in patients with NIDCM.

scholarly journals Serum autotaxin level predicts future cardiac events in patients with dilated cardiomyopathy

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
T Araki ◽  
T Okumura ◽  
T Mizutani ◽  
Y Kimura ◽  
S Kazama ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Dilated Cardiomyopathy ◽  
Volume Fraction ◽  
Left Ventricular ◽  
Cox Proportional Hazards ◽  
Left Ventricular Ejection ◽  
Myocardial Inflammation ◽  
Prognostic Impact ◽  
Cardiac Events ◽  
Ventricular Ejection Fraction

Abstract Background Autotaxin (ATX) has been reported to promote myocardial inflammation and subsequent cardiac remodeling through lysophosphatidic acid (LPA) production. However, the prognostic impact of ATX has not been clarified in dilated cardiomyopathy (DCM). Purpose We aimed to investigate the prognostic impact of ATX in patients with DCM. Methods We enrolled 104 DCM patients (49.8 years, 76 males). The subjects underwent blood sampling, echocardiography, cardiac catheterization, and endomyocardial biopsy. Gender differences in serum ATX levels have been reported, thus we divided the subjects into two groups using median serum ATX levels for men and women: High-ATX group and Low-ATX group. All patients were followed up by expert cardiologists. The cardiac event was defined as a composite of cardiac death and hospitalization for worsening heart failure. Results Eighty-nine percent of the subjects were classified as New York Heart Association functional class I or II. Female patients had higher serum ATX levels than male patients, with median values of 257.0 ng/mL and 203.5 ng/mL, respectively (Figure A). The average left ventricular ejection fraction and brain natriuretic peptide levels were 30.6% and 122.5 pg/mL. In survival analysis, cumulative event-free probability was significantly lower in High ATX group (p=0.007, Figure B). In Cox proportional hazards analysis, High-ATX was one of the independent predictors of composite cardiac events (Hazards Ratio, 2.575; p=0.043). On the other hand, high sensitive C-reactive protein and collagen volume fraction in myocardial samples were not significant predictors. Conclusion High serum ATX level was associated with poor prognosis in patients with DCM. FUNDunding Acknowledgement Type of funding sources: None. Gender difference in autotaxin levels Survival analysis of cardiac events

Innexin-3 forms connexin-like intercellular channels

1999 ◽  
Vol 112 (14) ◽  
pp. 2391-2396 ◽  
Author(s):  
Y. Landesman ◽  
T.W. White ◽  
T.A. Starich ◽  
J.E. Shaw ◽  
D.A. Goodenough ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Gap Junction ◽  
Functional Properties ◽  
Xenopus Oocytes ◽  
Family Members ◽  
Electrical Coupling ◽  
Large Family ◽  
Gap Junction Channel ◽  
Intercellular Channels

Innexins comprise a large family of genes that are believed to encode invertebrate gap junction channel-forming proteins. However, only two Drosophila innexins have been directly tested for the ability to form intercellular channels and only one of those was active. Here we tested the ability of Caenorhabditis elegans family members INX-3 and EAT-5 to form intercellular channels between paired Xenopus oocytes. We show that expression of INX-3 but not EAT-5, induces electrical coupling between the oocyte pairs. In addition, analysis of INX-3 voltage and pH gating reveals a striking degree of conservation in the functional properties of connexin and innnexin channels. These data strongly support the idea that innexin genes encode intercellular channels.

P6452Circulating human epididymis protein 4 is a novel prognostic predictor in ambulatory patients with non-ischemic dilated cardiomyopathy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T Okumura ◽  
H Oishi ◽  
T Kondo ◽  
Y Arao ◽  
H Kato ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Cardiac Catheterization ◽  
Coronary Sinus ◽  
Left Ventricular ◽  
Ascending Aorta ◽  
Left Ventricular Ejection ◽  
Composite Event ◽  
Ambulatory Patients ◽  
Non Ischemic Dilated Cardiomyopathy

Abstract Background Myofibroblasts, which are activated fibroblasts, play an important role in interstitial fibrosis in non-ischemic dilated cardiomyopathy (NIDCM). Recently, human epididymal body protein 4 (HE4) has attracted attention as a marker specific to myofibroblasts. However, the prognostic impact of HE-4 on cardiovascular events in NIDCM patients has not been reported. Purposes The purpose of this study was to investigate the impact of circulating serum HE4 on the prognosis in patients with NIDCM. Methods Forty-four NIDCM patients underwent echocardiography, laboratory measurements, cardiac catheterization, and endomyocardial biopsy within one week under stable heart failure condition. Patients with cancer were excluded from this study. We collected blood samples from peripheral vain, ascending aorta, and coronary sinus during cardiac catheterization and measured serum HE4 level. They were divided into two groups at the median of HE4 level: High-HE4 group (HE4 >69 pmol/L); n=22, Low-HE4 group (HE4 <69 pmol/L); n=22. Cardiac composite event was defined as cardiac related deaths and hospitalization due to worsening heart failure. Results The mean age, left ventricular ejection fraction (LVEF), and plasma brain natriuretic peptide level were 56 years, 32%, and 205 pg/mL. Between two groups, there were no significant differences in age, gender, LVEF, left ventricular end-diastolic diameter, cardiac index, and pulmonary capillary wedge pressure. However, estimated glomerular filtration rate was significantly lower in the High-HE4 group (p=0.025). Kaplan-Meier survival analysis revealed that the High-HE group had a higher rate of cardiac composite event (p=0.011, see Figure). However, as for the pathological analysis, not only the peripheral HE4 level but also HE4 value subtracting coronary sinus from ascending aorta did not significantly correlate with collagen volume fraction in biopsy samples. Circulating HE4 level and prognosis Conclusion Elevated circulating HE4 is associcated with poor prognosis in ambulatory patients with NIDCM.

scholarly journals Analysis of the incidence and baseline predictors of the left ventricular ejection fraction returning to normal after dilated cardiomyopathy in postmenopausal women: a retrospective, observational study

2020 ◽  
Vol 48 (5) ◽  
pp. 030006052092247
Author(s):  
Xiaopin Yuan ◽  
Shuai Mao ◽  
Qizhu Tang
Keyword(s):  
Left Ventricular Ejection Fraction ◽  
Ejection Fraction ◽  
Dilated Cardiomyopathy ◽  
Postmenopausal Women ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Ventricular Ejection ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
History Of

Objective To analyse the incidence and baseline predictors of the left ventricular ejection fraction (LVEF) returning to normal after dilated cardiomyopathy (DCM) following intervention with standard anti-heart failure (HF) medication in postmenopausal women. Methods Data from consecutive postmenopausal women who were first diagnosed with DCM and received anti-HF treatment during 2011 to 2018 were prospectively retrieved. The study population was divided into the LVEF recovery (LVR) group and the LVEF unrecovered (LVU) group according to whether LVEF was > 50%. The primary endpoint was baseline predictors of LVEF returning to normal. Results LVEF returned to normal in 49.3% (210/426) of patients with DCM. LVEF was significantly higher in the LVR group than in the LVU group (57.4% ± 6.9% vs 44.2% ± 5.3%; hazard ratio 1.312, 95% confidence interval 1.015–1.726) at the final follow-up. High systolic pressure, a short history of HF, a short QRS interval, a small left ventricular end-diastolic diameter (LVEDd), and high LVEF at admission were independent predictors of LVEF returning to normal. Conclusions LVEF returning to normal in postmenopausal women with DCM who receive standard anti-HF treatment is associated with systolic pressure, a history of HF, QRS interval, LVEDd, LVEF at admission, and favourable outcome.

P337Natural history, reversibility and arrhythmias associated with truncating titin variants in dilated cardiomyopathy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C R Vissing ◽  
T B Rasmussen ◽  
M S Olesen ◽  
L N Pedersen ◽  
A Dybro ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Medical Therapy ◽  
Ventricular Arrhythmias ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Reverse Remodeling ◽  
Absolute Increase ◽  
The Mean

Abstract Background Truncating genetic variants in titin (TTNtv) are identified in 15–25% of patients with primary dilated cardiomyopathy (DCM). Previous genotype/phenotype studies have reported conflicting results regarding disease severity and pathologic features associated with TTNtv. Purpose To investigate the natural history, reversibility and burden of arrhythmias associated with TTNtv in a Danish cohort with long-term follow-up. Methods Patients with DCM, recruited from two Danish tertiary centers, were included based on the presence of a TTNtv in a cardiac expressed titin exon. Data on patients' medical history including symptoms, demography, family history, comorbidities, treatment, ECG features, and echocardiograms were registered. Outcome data including all-cause mortality, need of heart transplantation (HTX) or left ventricular assist device (LVAD), and presence of ventricular and supraventricular arrhythmias were registered. Left ventricular reverse remodeling (LVRR) was defined as an absolute increase in left ventricular ejection fraction (LVEF) ≥10% points or normalization. Results A total of 104 patients (71 men, 69%; 72 probands) with definite TTNtv-DCM were included. The mean age at DCM diagnosis was (mean±SD) 45±13 years (43±13 for men; 49±14 for women, p<0.04) and median follow-up was 8.1 years. The mean LVEF was 28±13% at time of diagnosis (26±12% for men; 30±13% for women, p=0.173). During follow-up, 31 patients (30%; 24 men) died or needed HTX/LVAD. Medical therapy was associated with LVRR in 79% of patients 3.6 years after diagnosis. LVRR was maintained long-term in 64% of patients. Women had a better response to medical therapy compared to men (mean LVEF increase 19%; vs 15% in men, p<0.04). Atrial fibrillation/flutter was observed in 40% of patients and ventricular arrhythmias in 23% of patients. Men had an earlier occurrence of both supraventricular and ventricular arrhythmias (p=0.005) with half of the men having experienced an arrhythmia at the age of 54 years. Freedom from arrhythmias with age Conclusion TTNtv leads to a DCM phenotype associated with a marked gender-difference in age at DCM diagnosis and high burden of both supraventricular and ventricular arrhythmias. Importantly, the DCM-TTNtv phenotype was associated with a high degree of reversibility of systolic function following medical therapy.

P370Added value changes in signal sonr in patients with = <30% left ventricular ejection fraction

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
J J Garcia Guerrero ◽  
J Fernandez De La Concha Castaneda ◽  
A Chacon Pinero ◽  
J Garcia Fernandez ◽  
I Fernandez Lozano ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Hospital Admission ◽  
Dilated Cardiomyopathy ◽  
Interim Analysis ◽  
Cardiac Contractility ◽  
Inverse Correlation ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Lv Ejection Fraction

Abstract Abstract/Introduction Decompensated congestive heart failure (CHF) is a main and increasing health problem worldwide, which leads to patients’ bad outcomes and high money expenditure. Direct relationship between Brain Natriuretic Peptides (NT-proBNP) increasing levels and adverse clinical outcomes have been demonstrated in patients with CHF.  SonR signal sensor, a micro-accelerometer embedded in the tip of the atrial lead in patients implanted with devices, picks up cardiac muscle vibration. Its amplitude is a surrogate for cardiac contractility, which is found to be further reduced in patients with decompensated CHF. Purpose We sought to find a significant inverse correlation between SonR signal and NT-proBNP levels, in order to use SonR as a surrogate of NT-proBNP to anticipate worsening CHF leading to hospital admission. Methods AVCs SONR trial is a pilot, prospective, observational, multicentre study, in which patients with dilated cardiomyopathy, any aetiology, LV ejection fraction ≤ 30%, at least one recent (&lt; 1 year) hospital admission due to CHF, and implanted with CRT-D devices (used as dual-chamber, no left ventricular (LV) lead implanted) with SonR sensor feature, were enrolled. During a year, NT-proBNP and SonR values were obtained every month, and both levels compared (Pearson’s test) Results This an interim analysis of our data, 18 months after the first patient was enrolled. Twenty two patients and 116 data pairs were analysed. Most patients were men (91%) and had ischemic dilated cardiomyopathy (59%). Mean age was 61 (range 34-82) and mean LV ejection fraction was 27% (range 15-30). The mean Pearson’s correlation coefficient of the NT-proBNP values and the SonR signal was r = - 0.36 (95% CI -0.51 to -0.19), p &lt; 0.00006 (Figure) Conclusions The interim analysis of this study shows an inverse and very significant relationship between SonR signal and NT-proBNP values. This suggests SonR signal might be used as predictor of worsening CHF. Abstract Figure

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