Genetic variants in calcium regulatory cardiac genes and their contribution to Takotsubo syndrome

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F Treu ◽  
N Dybkova ◽  
P Jung ◽  
Y Li ◽  
D Huebscher ◽  
...  
Keyword(s):  
Genetic Predisposition ◽  
Genetic Variants ◽  
Left Ventricular ◽  
Calcium Currents ◽  
Epifluorescence Microscopy ◽  
Patient Specific ◽  
Funding Source ◽  
Sequencing Analysis ◽  
Takotsubo Syndrome ◽  
Calcium Load

Abstract Background and purpose Takotsubo syndrome (TTS) is characterized by an acute left ventricular dysfunction similar to a myocardial infarction (MI) in the absence of coronary artery stenosis. Patients show symptoms similar to the acute MI with increased biomarkers and blood serum catecholamines. Recently, we developed a patient-specific TTS stem cell model and identified a higher sensitivity to catecholamine-induced stress. Furthermore, familial TTS cases and genetic studies point to a genetic predisposition. The purpose of this study was to analyze a genetic predisposition by characterizing genetic variants in genes associated with cardiac pathologies and their impact on calcium homoeostasis in TTS. Methods and results Whole exome sequencing analysis of a TTS patient discovered 2 missense AHNAK variants in its C-terminal domain and in addition the missense variant F189L in the calcium buffering calsequestrin 2 gene (CASQ2). AHNAK is a 700kDa big nucleoprotein and is involved in the β-adrenergic regulation of the cardiac calcium channel Cav1.2. 3-month old TTS-iPSC-derived cardiomyocytes (CM) were generated and the variants were confirmed by sequencing. We found AHNAK higher expressed in TTS-iPSC-CMs compared to control, whereas no expression alteration was observed for Cav1.2. Since AHNAK is described to act as a repressor towards Cav1.2, which is relieved under β-adrenergic stimulation, we analyzed the effect of AHNAK variants on a potential co-localization and interaction between both proteins. AHNAK and Cav1.2 were shown to co-localize in the cytoplasm as well as the membranes and co-immunoprecipitation experiments confirmed an interaction of AHNAK and Cav1.2 in all tested control- and TTS-iPSC-CMs. On a functional level, we were able to show by patch clamp analysis that Cav1.2 calcium currents are significantly increased in TTS-iPSC-CMs compared to control. The influence of CASQ2-F189L on sarcomeric reticulum (SR) calcium load was analyzed by epifluorescence microscopy using FURA4 and caffeine-applications. We found significantly decreased SR calcium content with an increased fractional release during systole in TTS-iPSC-CMs. To test, whether these variants are the main reason for altered interaction of AHNAK and Cav1.2, calcium currents or SR calcium load in TTS need to be proven in the future by using CRISPR/Cas9-rescued AHNAK/CASQ2 lines. Conclusion Here we show the cardiac functional consequences of AHNAK and CASQ2 missense mutations in TTS-iPSC-CMs with regard to calcium currents and SR calcium load. These results show that AHNAK and CASQ2 variants may predispose to TTS and enable a new therapeutic option for TTS. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Else Kröner-Fresenius Foundation

Role of phosphodiesterases in the development of takotsubo syndrome

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D Huebscher ◽  
T Borchert ◽  
G Hasenfuss ◽  
V.O Nikolaev ◽  
K Streckfuss-Boemeke
Keyword(s):  
Resonance Energy ◽  
Induced Pluripotent Stem Cell ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Left Ventricular ◽  
Camp Level ◽  
Camp Signaling ◽  
Patient Specific ◽  
Funding Source ◽  
Takotsubo Syndrome

Abstract Background/Purpose Takotsubo syndrome (TTS) is characterized by acute transient left ventricular dysfunction in the absence of obstructive coronary lesions. We identified a higher sensitivity to catecholamine-induced stress toxicity as mechanism associated with the TTS phenotype in our former study, but the pathogenesis of TTS is still not completely understood. In this study our aim was to prove the hypothesis of an altered phosphodiesterase (PDE)-dependent 3',5'-cyclic adenosine monophosphate (cAMP)-signaling in TTS in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Methods and results We generated functional TTS-iPSC-CMs and treated them with catecholamines to mimic a TTS-phenotype. To directly address the hypothesis that local cAMP dynamics might be altered in TTS, we used Förster resonance energy transfer (FRET) based cAMP sensors, which are specifically located in the cytosol or at the sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA) micro domain. We demonstrated that β-adrenergic receptor (β-AR) stimulations resulted in stronger cytosolic FRET responses in TTS-CMs compared to controls. In contrast, no differences of cAMP level were observed in the SERCA-PLN micro domain between TTS- and control-iPSC-CMs. To analyze the interplay of β-AR signaling and specific PDE contribution to the cAMP signaling in TTS, specific PDE-inhibitors were used. We were able to show in the cytosol that after β-AR stimulation, the strong effects of the PDE4 family of control cells were significantly decreased in diseased TTS CMs, which is in line with previously described reduced PDE4 activity in failing mouse hearts. In contrast, the contribution of PDE3 to cytoplasmic cAMP degradation was increased in TTS (Figure 1 A). This is in line with increased PDE3A and down-regulated PDE4D protein expression in TTS-iPSC-CMs compared to control cells. Analysis of PDE-dependent cAMP level in the SERCA micro domain show also a significantly reduced PDE4 activity. But the dynamic cytosolic PDE contribution of PDE2 and PDE3 after catecholamine treatment in TTS is lost in SERCA micro domain (Figure1B). Conclusion Our data showed for the first time alterations of local cAMP signaling in healthy and diseased TTS-iPSC-CMs. We demonstrated an isozym shift from PDE4 in control to PDE3 and PDE2 in TTS and identified PDE4 as an important player in the β-adrenergic cAMP signaling in TTS. Therefore, PDE4 activators may be a possible new therapeutic target option in the treatment of TTS. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): DZHK

scholarly journals Takotsubo Syndrome: Contemporary Views on the Pathogenesis, Prevalence and Prognosis

2018 ◽  
Vol 14 (4) ◽  
pp. 598-604 ◽  
Author(s):  
A. S. Shilova ◽  
A. O. Shmotkina ◽  
A. A. Yafarova ◽  
M. Yu. Gilyarov
Keyword(s):  
Genetic Predisposition ◽  
Randomized Clinical Trials ◽  
Myocardial Dysfunction ◽  
Specific Treatment ◽  
Left Ventricular ◽  
Takotsubo Syndrome ◽  
St Segment Elevation ◽  
Coronary Syndrome ◽  
St Segment ◽  
Reversible Left Ventricular Dysfunction

Takotsubo syndrome (TTS) is a reversible left ventricular dysfunction characterized by local apical hypokinesia usually triggered by a physical or emotional stress. According to the last available data TTS may represent 2% of all admissions for acute coronary syndromes. Despite the reliable prevalence, diagnosis of TTS remains difficult. The initial presentation, both clinically and electrocardiographically, is similar to an acute myocardial infarction (AMI). The biomarker profile is also similar, although the peaks of troponin and creatinine kinase levels are lower, and brain natriuretic peptide levels are higher in patients with TTS compared with ST-segment elevation AMI. Modified Mayo diagnostic criteria are the most common for the diagnosis. Pathogenesis of TTS currently is not well understood. Catecholamines appear to play a central role in the pathophysiology of TTS. However, it is conceivable that some people have a genetic predisposition to stress-induced TTS. A genetic predisposition has been suggested based on the few familial TTS cases described. Despite reversible myocardial dysfunction, acute heart failure is the most common complication in the acute phase of TTS. In-hospital mortality rate is comparable to that of ST-segment elevation AMI. There are no randomized clinical trials to support specific treatment recommendations in TTS. It is believed that the tactics of managing patients with TTS hospitalized with suspicion of acute coronary syndrome should comply with the protocol of management of patients with AMI while acute coronary pathology is not excluded.

scholarly journals Dysfunctional crosstalk of cardiomyocytes and cardiac fibroblasts in a pluripotent stem cell model of dilated cardiomyopathy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
W Maurer ◽  
S Koehne ◽  
A Maus ◽  
M Tiburcy ◽  
S Schlick ◽  
...  
Keyword(s):  
Stem Cell ◽  
Dilated Cardiomyopathy ◽  
Pluripotent Stem Cell ◽  
Cell Model ◽  
Cardiac Fibroblasts ◽  
Left Ventricular ◽  
Patient Specific ◽  
Funding Source ◽  
New Variant ◽  
Healthy Control

Abstract Background/Purpose Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and contractile dysfunction. Fibrosis is one major phenotypic result in DCM, pointing to the contribution of both, cardiomyocytes (CM) and cardiac fibroblasts (cFB) to DCM. The molecular basis of most DCM cases remains unknown. Nevertheless, it is known that up to 35% of all cases have a family history, linked to mutations in more than 30 gene loci. The aim of this study is to analyse the crosstalk of iPSC-CM and cFB and the underlying genetic and molecular causes in a patient-specific induced pluripotent stem cell (iPSC) model of DCM. Methods and results For this purpose a 4-member family was recruited containing 2 patients (father and daughter) with severe DCM and heart transplantation. iPSCs of all family members were generated and differentiated into iPSC-CMs. All iPSC-CMs express general cardiac markers, e.g. βMHC, α-actinin. Interestingly, αMHC expression was decreased in diseased iPSC-CMs in comparison to control cells. Additionally, the sarcomeric regularity was decreased in diseased iPSC-CMs. As we found significantly increased fibrosis (22%) in explanted myocardium of the diseased father compared to healthy myocardium (8%), both cFB and CM seem to play an important role. From the same myocardium primary cFBs were isolated and shown to express typical cFB markers clearly distinguishing these cells from non-fibroblasts as well as from fibroblasts with different origin. To analyse the contribution of cFBs and CMs to DCM on a functional level, 3D engineered heart muscles (EHMs) were generated in different diseased/healthy cell combinations. EHMs composed of both or either one affected DCM-iPSC-CMs and/or DCM-cFBs in comparison to healthy control EHMs did not produce any measurable force, indicating that the DCM-EHM phenotype is clearly diseased. Evaluation of tissues' viscoelasticity showed that DCM-cFB, DCM-iPSC-CMs and DCM-EHMs were stiffer than healthy control EHMs. Thus these data suggest that apart from the obvious dysfunction of DCM CMs, DCM cFBs clearly contribute to the contractile pathophysiology in DCM EHMs. Furthermore, whole exome sequencing of iPSCs was conducted to identify disease-causing variants. This analyses point towards a new genetic variant in the FLNc gene coding for a protein important in development, stabilization and maintenance of myofibrils. Rescue of this variant by CRISPR Cas9 genome editing will shed more light onto the role of this variant during DCM development in the future. Conclusion Using a ps-iPSC-CM model of a 4-member family with two severe DCM patients, we could demonstrate a clear contribution of both cell types, iPSC-CMs and cFB, to the contractile pathophysiology of DCM. We identified a potentially disease-causing new variant in the FLNc gene, which may contribute to the impaired functionality within the diseased iPSC-CMs and EHM. This makes FLNc a new therapeutic target for DCM. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): IRTG1816

RBM20-mutations induce disturbed splicing of calcium relevant genes in patient-specific stem cell models of cardiomyopathies

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Rebs ◽  
F Sedaghat-Hamedani ◽  
E Kayvanpour ◽  
D Huebscher ◽  
H Katus ◽  
...  
Keyword(s):  
Stem Cell ◽  
Alternative Splicing ◽  
Molecular Mechanisms ◽  
Cell Model ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Patient Specific ◽  
Funding Source ◽  
Cardiac Phenotype

Abstract Background and aim Mutations in the splice factor RBM20 have been identified to account for ∼3% of cardiomyopathies. In particular, the highly conserved RS-domain is a hotspot for disease-associated mutations. Distinct mutations at position 634 in the RS-domain were already described to be associated to dilative cardiomyopathy (DCM) (R634W) or to left ventricular non-compaction cardiomyopathy (LVNC) (R634L), but the molecular mechanisms that govern the heterogenic entity of DCM and LVNC remain largely unknown. We aimed to analyze the molecular driver behind the RBM20 mutation-based DCM and LVNC in a patient-specific stem cell model. Methods Human somatic cells from 2 DCM- and 2 LVNC-patients harboring the RBM20-mutations R634W (DCM) or R634L (LVNC) were reprogrammed into induced pluripotent stem cells (iPSC) and differentiated into functional cardiomyocytes (CM). Gene expression, alternative splicing activity, sarcomeric regularity, cAMP level, kinase-specific phosphorylation of important Ca2+ players, and physiological cardiac functions as Ca2+ homeostasis were analyzed (Fluo3 and Fura4). Isogenic rescue lines were generated by CRISPR/Cas9 technology to analyze the direct impact of the RBM20 mutations to the cardiac phenotype. Results We investigated the role of RBM20 mutations in DCM and LVNC-iPSC-CMs RBM20-splicing and observed common splice defects in titin-isoform-switch or a 24bp insertion in the gene ryanodine receptor 2 (RYR2).. In contrast, the calcium-handling gene Camk2δ was predominantly mis-spliced in LVNC-CMs, whereas the structural gene LDB3 was mis-spliced in DCM-CMs. As a possible consequence of splice defects in sarcomeric genes both DCM and LVNC-CMs exhibited an irregular sarcomeric structure at the Z-disk and M-line. Interestingly, the LVNC-CMs showed faster Ca2+ transient decay time and weakened response to β-adrenergic stimulation. In contrast, the DCM-CMs did exhibit increased Ca2+-sparks and decreased systolic and diastolic Ca2+ highlighting that two distinct missense mutations can lead to different pathological Ca2+ phenotypes. Ca2+ kinetic defects in LVNC-iPSC-CMs were independent of cAMP, but in line with Camk2δ-dependent hyperphosphorylation of the specific target PLN. Isogenic WT-iPSC lines were generated using CRISPR/Cas9 technology and underscored the role of RBM20-mutations in cardiomyopathies as the sarcomeric defects, Ca2+ cycling and leakage were rescued for both LVNC-CMs and DCM-CMs. Conclusion We show the first iPSC-model of splice-defect-associated RBM20-dependent LVNC and DCM. Our data demonstrate that RBM20-R634L induce mis-splicing of Camk2δ leading to hyperphosphorylation of PLN-Thr17 along with increased Ca2+ kinetics in LVNC, whereas RBM20-R634W induced RYR2-dependent Ca2+ leak with disturbed systolic and diastolic Ca2+in DCM. Taken together these results suggest that the molecular aberrations in alternative splicing differ depending on the distinct missense mutation in RBM20. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): BMBF, DZHK German Center for Cardiovascular research

Cardiac Resynchronisation Therapy – Evolving Strategies to Enhance Response

2010 ◽  
Vol 6 (1) ◽  
pp. 83
Author(s):  
Jagmeet P Singh ◽  
Keyword(s):  
Heart Failure ◽  
Systolic Heart Failure ◽  
Cardiac Resynchronisation Therapy ◽  
Left Ventricular ◽  
Patient Specific ◽  
Cardiac Resynchronisation ◽  
Clinical Benefits ◽  
Pacing Lead ◽  
Resynchronisation Therapy ◽  
Physiological Impact

Cardiac resynchronisation therapy (CRT) has gained widespread acceptance as a safe and effective therapeutic strategy for congestive heart failure (CHF) refractory to optimal medical therapy. The use of implantable devices has substantially altered the natural history of systolic heart failure. These devices exert their physiological impact through ventricular remodelling, associated with a reduction in left ventricular (LV) volumes and an improvement in ejection fraction (EF). Several prospective randomised studies have shown that this in turn translates into long-term clinical benefits such as improved quality of life, increased functional capacity and reduction in hospitalisation for heart failure and overall mortality. Despite these obvious benefits, there remain more than a few unresolved concerns, the most important being that up to one-third of patients treated with CRT do not derive any detectable benefit. There are several determinants of successful delivery and response to CRT, including selecting the appropriate patient, patient-specific optimal LV pacing lead placement and appropriate post-implant device care and follow-up. This article highlights the importance of collectively working on all of these aspects of CRT to enhance and maximise response.

AIM2-driven inflammasome activation in chronic heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Ruppert ◽  
Z.S Onodi ◽  
P Leszek ◽  
V.E Toth ◽  
G Koncsos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Animal Models ◽  
Left Ventricular ◽  
Inflammasome Activation ◽  
Coronary Artery Ligation ◽  
Funding Source ◽  
Human Cardiomyocytes ◽  
Pannexin 1 ◽  
End Stage

Abstract Background Inflammation and cytokine release have been implicated in the pathogenesis of chronic heart failure (CHF). Of particular interest, Canakinumab, a monoclonal antibody against interleukin-1b (IL-1β), had provided benefit against cardiovascular events, suggesting that blockade of IL-1β secretion and signaling might be a promising new therapeutic target. Although, recent studies have provided evidence that inflammasome activation is the main contributor to IL-1β maturation, the role of inflammasome activation in CHF remains unknown. Objective Therefore, we aimed to assess inflammasome activation in myocardial samples from end-stage failing hearts. Methods Inflammasome activation was assessed by immunoblotting in left ventricular myocardial specimens harvested from patients with end-stage CHF. Furthermore, immunoblot measurements were also performed on translational animal models of CHF (e.g. rat models of permanent coronary artery ligation and transverse aortic constriction). Left ventricular monocyte and macrophage infiltration was detected by immunohistochemistry. To investigate the molecular background of inflammasome activation, a series of cell culture experiments were performed on AC16 human cardiomyocytes and THP-1 human monocytic cell lines. Results Out of the 4 major inflammasome sensors tested, expression of the inflammasome protein absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) increased in human CHF while the NLRP1 and NLRP3 (NLR family, pyrin domain containing 1 and 3) inflammasome showed no change. A similar expression pattern in AIM2 and NLRC4 was also noted in CHF animal models. Furthermore, robust infiltration of Iba1+ monocytes/macrophages was observed in human failing hearts as well as in different animal models of CHF. In vitro AIM2 inflammasome activation, as induced by transfection with double-stranded DNA [poly(deoxyadenylic-deoxythymidylic)] was reduced significantly by the pharmacological blockade of pannexin-1 channels. Conclusions AIM2 and NLRC4 inflammasome activation might contribute to chronic inflammation in CHF. Our findings suggest that pannexin-1 channels might be a promising novel target to reduce inflammasome activation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

Randomized, double blind, placebo-controlled, safety and efficacy study of dutogliptin in combination with filgrastim in early recovery post-MI: rationale, design and first interim analysis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D Von Lewinski ◽  
B Merkely ◽  
I Buysschaert ◽  
R.A Schatz ◽  
G.G Nagy ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Stem Cells ◽  
Adverse Events ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Funding Source ◽  
Early Recovery ◽  
Ventricular Ejection Fraction ◽  
Combined Application

Abstract Background Regenerative therapies offer new approaches to improve cardiac function after acute ST-elevation myocardial infarction (STEMI). Mobilization of stem cells and homing within the infarcted area have been identified as the key mechanisms for successful treatment. Application of granulocyte-colony stimulating factor (G-CSF) is the least invasive way to mobilize stem cells while DDP4-inhibitor facilitates homing via stromal cell-derived factor 1 alpha (SDF-1α). Dutogliptin, a novel DPP4 inhibitor, combined with stem cell mobilization using G-CSF significantly improved survival and reduced infarct size in a murine model. Purpose We initiated a phase II, multicenter, randomized, placebo-controlled efficacy and safety study (N=140) analyzing the effect of combined application of G-CSF and dutogliptin, a small molecule DPP-IV-inhibitor for subcutaneous use after acute myocardial infarction. Methods The primary objective of the study is to evaluate the safety and tolerability of dutogliptin (14 days) in combination with filgrastim (5 days) in patients with STEMI (EF <45%) following percutaneous coronary intervention (PCI). Preliminary efficacy will be analyzed using cardiac magnetic resonance imaging (cMRI) to detect >3.8% improvement in left ventricular ejection fraction (LV-EF). 140 subjects will be randomized to filgrastim plus dutogliptin or matching placebos. Results Baseline characteristics of the first 26 patients randomized (24 treated) in this trial reveal a majority of male patients (70.8%) and a medium age of 58.4 years (37 to 84). During the 2-week active treatment period, 35 adverse events occurred in 13 patients, with 4 rated as serious (hospitalization due to pneumonia N=3, hospitalization due to acute myocardial infarction N=1), and 1 adverse event was rated as severe (fatal pneumonia), 9 moderate, and 25 as mild. 6 adverse events were considered possibly related to the study medication, including cases of increased hepatic enzymes (N=3), nausea (N=1), subcutaneous node/suffusion (N=1) and syncope (N=1). Conclusions Our data demonstrate that the combined application of dutogliptin and G-CSF appears to be safe on the short term and feasible after acute myocardial infarction and may represent a new therapeutic option in future. Funding Acknowledgement Type of funding source: Other. Main funding source(s): This research is funded by the sponsor RECARDIO, Inc., 1 Market Street San Francisco, CA 94150, USA. RECARDIO Inc. is funding the complete study. The Scientific Board of RECARDIO designed the study. Data Collection is at the participating sites. Interpretation of the data by the Scientific Board and Manuscript written by the authors and approved by the Sponsor

Mechanisms of angina in patients with biopsy-proven viral myocarditis: insights from intracoronary acetylcholine testing

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Seitz ◽  
V Martinez Pereyra ◽  
A Hubert ◽  
K Klingel ◽  
R Bekeredjian ◽  
...  
Keyword(s):  
Coronary Arteries ◽  
Coronary Spasm ◽  
Viral Myocarditis ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Funding Source ◽  
Pathophysiological Mechanism ◽  
Ecg Changes ◽  
Ventricular Ejection Fraction ◽  
Microvascular Spasm

Abstract Background Patients with myocarditis often present with angina pectoris despite unobstructed coronary arteries. The underlying pathophysiological mechanism of angina in these patients remains to be elucidated. Coronary artery spasm is a well-known cause of angina in patients with unobstructed coronary arteries. In this study, we sought to assess the frequency of coronary vasomotor disorders in patients with biopsy-proven viral myocarditis. Methods In total, 700 consecutive patients who underwent endomyocardial biopsy for suspected myocarditis between 2008 and 2018 were retrospectively screened. Of these patients, viral myocarditis was confirmed in 303 patients defined as histological/immunohistological evidence of myocardial inflammation and presence of viral genome confirmed by PCR. Of these patients, 34 patients had angina despite unobstructed coronary arteries and underwent intracoronary acetylcholine (ACh) provocation testing in search of coronary spasm. Epicardial spasm was defined as acetylcholine-induced reproduction of the patient's symptoms associated with ischemic ECG changes and >90% epicardial vasoconstriction. Microvascular spasm was defined as symptom reproduction and ECG changes in the absence of significant epicardial vasoconstriction. Results Patients were 49±16 years old, 62% were male and left ventricular ejection fraction was 54±16%. Most frequent viruses were parvovirus B19 (PVB19, 59%) and human herpes virus 6 (HHV6, 26%), 2 patients had combined PVB19/HHV6 infection and 3 patients other herpesviruses (CMV, EBV, VZV). Epicardial spasm was observed in 10 patients (29%) during ACh testing and microvascular spasm was found in 11 patients (32%). The rate of coronary spasm (epicardial and microvascular) was higher in the PVB19 subgroup compared to HHV6 (80% vs. 33%, p=0.031). In particular, there was a higher prevalence of microvascular spasm in PVB19 compared to HHV6 (45% vs. 0%, p=0.018). Conclusion We observed a high prevalence of microvascular and epicardial spasm in patients with biopsy-proven viral myocarditis suggesting coronary spasm as a potential underlying mechanism for angina in these patients. Microvascular spasm was most often observed in patients with PVB19-associated myocarditis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Robert-Bosch-Stiftung; Berthold-Leibinger-Stiftung

Genetic polymorphisms and cardiovascular outcomes in Chinese patients undergoing PCI and treated with clopidogrel and aspirin

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K Xu ◽  
L Ying ◽  
J Chen ◽  
L Xu ◽  
J Li ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Genetic Polymorphisms ◽  
Light Transmission ◽  
Left Ventricular ◽  
Cardiovascular Outcomes ◽  
Chinese Patients ◽  
Left Ventricular Ejection ◽  
Funding Source ◽  
Ventricular Ejection Fraction ◽  
One Year

Abstract Background Genetic polymorphisms of key proteins involved in clopidogrel absorption, metabolism, and action may contribute to variability in platelet inhibition in patients undergoing percutaneous coronary intervention (PCI), but their impacts on cardiovascular outcomes remain unclear. Purpose To examine the associations between genetic polymorphisms and cardiovascular outcomes in Chinese patients undergoing PCI and treated with clopidogrel and aspirin. Methods This prospective cohort study consecutively enrolled 2,453 post-PCI patients treated with clopidogrel and aspirin. Adenosine diphosphate-induced platelet aggregation was measured by light transmission aggregometry. A total of 40 single nucleotide polymorphisms (SNPs) of 18 genes selected according to published studies were investigated using an improved multiplex ligation detection reaction technique. The primary outcome was major adverse cardiovascular event (MACE), the composite of cardiovascular death, non-fatal myocardial infarction (MI), and ischemic stroke within one year after PCI. Results We restricted the analyses to the first 1,452 patients who had finished one-year follow-up and complete data on genotyping and platelet aggregation. 44 (3.03%) patients suffered MACE. Among the 40 SNPs, only the A-allele carriers of CYP2C19*2 had a significant higher risk of MACE (adjusted HR 2.05; 95% CI, 1.01–4.19; p=0.048) and platelet aggregation than non-A-carriers after adjusting age, sex, MI presentation, and left ventricular ejection fraction. CYP2C19*3, CYP2B6 rs3745274, and PEAR1 rs12041331 variants were also significantly associated with platelet aggregation (all p<0.05) but not with MACE at 1 year. Conclusion About 54.2% of Chinese patients with PCI were A-allele carriers of CYP2C19*2, who face a two-fold higher risk of MACE than non-A-allele carriers in Chinese patients after PCI. It would help identify low clopidogrel responders and optimize antiplatelet therapy before drug administration. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Natural Science Funding of China

Prevalence and prognostic impact of left ventricular systolic dysfunction after acute myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T.J Jernberg ◽  
E.O Omerovic ◽  
E.H Hamilton ◽  
K.L Lindmark ◽  
L.D Desta ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Myocardial Infarction ◽  
Atrial Fibrillation ◽  
Risk Factor ◽  
Reperfusion Therapy ◽  
Left Ventricular ◽  
Funding Source ◽  
Additional Risk Factor ◽  
Additional Risk

Abstract Background Left ventricular dysfunction after an acute myocardial infarction (MI) is associated with poor outcome. The PARADISE-MI trial is examining whether an angiotensin receptor-neprilysin inhibitor reduces the risk of cardiovascular death or worsening heart failure (HF) in this population. The aim of this study was to examine the prevalence and prognosis of different subsets of post-MI patients in a real-world setting. Additionally, the prognostic importance of some common risk factors used as risk enrichment criteria in the PARADISE-MI trial were specifically examined. Methods In a nationwide myocardial infarction registry (SWEDEHEART), including 87 177 patients with type 1 MI between 2011–2018, 3 subsets of patients were identified in the overall MI cohort (where patients with previous HF were excluded); population 1 (n=27 568 (32%)) with signs of acute HF or an ejection fraction (EF) <50%, population 2 (n=13 038 (15%)) with signs of acute HF or an EF <40%, and population 3 (PARADISE-MI like) (n=11 175 (13%)) with signs of acute HF or an EF <40% and at least one risk factor (Age ≥70, eGFR <60, diabetes mellitus, prior MI, atrial fibrillation, EF <30%, Killip III-IV and STEMI without reperfusion therapy). Results When all MIs, population 1 (HF or EF <50%), 2 (HF or EF <40%) and 3 (HF or EF <40% + additional risk factor (PARADISE-MI like)) were compared, the median (IQR) age increased from 70 (61–79) to 77 (70–84). Also, the proportion of diabetes (22% to 33%), STEMI (38% to 50%), atrial fibrillation (10% to 24%) and Killip-class >2 (1% to 7%) increased. After 3 years of follow-up, the cumulative probability of death or readmission because of heart failure in the overall MI population and in population 1 to 3 was 17.4%, 26.9%, 37.6% and 41.8%, respectively. In population 2, all risk factors were independently associated with death or readmission because of HF (Age ≥70 (HR (95% CI): 1.80 (1.66–1.95)), eGFR <60 (1.62 (1.52–1.74)), diabetes mellitus (1.35 (1.26–1.44)), prior MI (1.16 (1.07–1.25)), atrial fibrillation (1.35 (1.26–1.45)), EF <30% (1.69 (1.58–1.81)), Killip III-IV (1.34 (1.19–1.51)) and STEMI without reperfusion therapy (1.34 (1.21–1.48))) in a multivariable Cox regression analysis. The risk increased with increasing number of risk factors (Figure 1). Conclusion Depending on definition, post MI HF is present in 13–32% of all MI patients and is associated with a high risk of subsequent death or readmission because of HF. The risk increases significantly with every additional risk factor. There is a need to optimize management and improve outcomes for this high risk population. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Novartis

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