PLK2 is a novel regulator of osteopontin-driven fibrosis and diastolic dysfunction in permanent atrial fibrillation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Kuenzel ◽  
E Klapproth ◽  
K Kuenzel ◽  
C Piorkowski ◽  
M Mayr ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Diastolic Heart Failure ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Knockout Mouse Model ◽  
Ventricular Diastolic Dysfunction

Abstract Background and aim Atrial fibrillation (AF) is frequently accompanied by cardiac fibrosis and diastolic heart failure. Due to the heterogeneous nature and complexity of fibrosis, the knowledge of the underlying pathomechanisms is limited. Thus, effective antifibrotic pharmacotherapy is missing. The objective of this study was to decipher the role of polo-like kinase 2 (PLK2) in the pathogenesis of cardiac fibrosis and left ventricular diastolic dysfunction. We put particular emphasis on the identification of profibrotic downstream targets of PLK2, which can serve as therapeutic targets. Methods and results This study was based on human atrial tissue biopsies and peripheral blood samples, a PLK2 knockout mouse model, a canine tachy-pacing model and specific pharmacological interventions on cardiac fibroblasts. In human atrial AF tissue samples, PLK2 was 50% downregulated by hypoxia-induced promoter methylation compared to sinus rhythm (SR) control. Confirmatory analysis of a canine tachy-pacing model showed PLK2 downregulation exclusively in the atria but not in the ventricles. Specific pharmacological inhibition as well as genetic deletion of PLK2 led to a striking myofibroblast phenotype. Discovery proteomics revealed that the global knockout of PLK2 resulted in de novo secretion of the inflammatory cytokine osteopontin (OPN) in cardiac fibroblasts and concomitant ventricular fibrosis in the PLK2 knockout mouse model. An ELISA analysis of peripheral blood samples of AF patients with electrophysiologically proven fibrosis, confirmed significantly increased OPN plasma concentrations compared to SR and non-fibrosis AF controls. Consequently, echocardiography on PLK2 KO mice revealed left ventricular diastolic dysfunction, tachycardia and fibrosis-typical surface ECG anomalies (PQ and QRS prolongation). Mechanistically, we identified the ERK1/2 signaling pathway as the molecular link between reduced expression of PLK2 and elevated osteopontin transcription. In a reverse translational attempt, we successfully tested the capability of 5-amino-salicylic acid (5-ASA) to inhibit osteopontin transcription and to reverse a TGF-β-induced myofibroblast phenotype in vitro. Currently the long-term administration of 5-ASA is tested in PLK2 knockout mice to evaluate the therapeutic potential to prevent cardiac fibrosis and diastolic heart failure development. Conclusion and clinical impact We identified PLK2 as an epigenetically regulated kinase involved in the pathophysiology of fibrosis in AF. PLK2 knockout mice can serve as a model of diastolic heart failure wherein OPN is a promising therapeutic target. Our results strengthen the current hypothesis that atrial fibrillation is not only an ion channel disease but a complex systemic disorder. Restoration of physiological PLK2 expression and blockade of osteopontin release with 5-ASA may constitute valuable new drug targets for the prevention and treatment of fibrosis and diastolic heart failure in AF. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Faculty of Medicine, Carl Gustav Carus, Dresden, “MeDDrive Start” Grant

Investigation of the Relationship Between Color M-Mode Early Diastolic Propagation Velocity and Left Ventricular Adverse Pressure Gradients

2010 ◽  
Author(s):  
Kelley C. Stewart ◽  
Rahul Kumar ◽  
John J. Charonko ◽  
Pavlos P. Vlachos ◽  
William C. Little
Keyword(s):  
Heart Failure ◽  
Diastolic Dysfunction ◽  
Diastolic Heart Failure ◽  
Diagnostic Techniques ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Pressure Gradients ◽  
Compensatory Mechanisms ◽  
Ventricular Diastolic Dysfunction ◽  
The Relationship

Left ventricular diastolic dysfunction (LVDD) and diastolic heart failure are conditions that affect the filling dynamics of the heart and affect 36% of patients diagnosed with congestive heart failure [1]. Although this condition is very prevalent, it currently remains difficult to diagnose due to inherent atrio-ventricular compensatory mechanisms including increased heart rate, increased left ventricular (LV) contractility, and increased left atrial pressure (LA). A greater comprehension of the governing flow physics in the left ventricle throughout the introduction of the heart’s compensatory mechanisms has great potential to substantially increase the understanding of the progression of diastolic dysfunction and in turn advance the diagnostic techniques.

scholarly journals Left Ventricular Diastolic Dysfunction In Hypertension, Diabetes Mellitus And Ischaemic Heart Disease

2004 ◽  
Vol 3 (3) ◽  
pp. 5-6
Author(s):  
RK Shah ◽  
AB Upadhayaya ◽  
L.P. Tibrewala ◽  
P.R. Regmi ◽  
K.P. Acharya ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Dysfunction ◽  
Diagnostic Criteria ◽  
Diastolic Heart Failure ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Significant Morbidity ◽  
Ventricular Diastolic Dysfunction ◽  
Definition Of ◽  
Standardized Diagnostic

Congestive heart failure caused by a predominant abnormality in diastolic function is both common and causes significant morbidity and mortality. However, there is a continued controversy surroundings the definition of diastolic dysfunction and the diagnostic criteria for diastolic heart failure. Recent clinical studies have provided sufficient data to develop standardized diagnostic criteria to define diastolic heart failure.

Estimation of Left Ventricular Wall Stiffness by Analysis of Late Diastolic Pressure Components

2011 ◽  
Author(s):  
Casandra L. Niebel ◽  
Kelley C. Stewart ◽  
Takahiro Ohara ◽  
John J. Charonko ◽  
Pavlos P. Vlachos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricle ◽  
Diastolic Dysfunction ◽  
Diastolic Pressure ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Ventricular Wall ◽  
Ventricular Relaxation ◽  
Wall Stiffness ◽  
Ventricular Diastolic Dysfunction

Left ventricular diastolic dysfunction (LVDD) is any abnormality in the filling of the left ventricle and is conventionally evaluated by analysis of the relaxation driven phase, or early diastole. LVDD has been shown to be a precursor to heart failure and the diagnosis and treatment for diastolic failure is less understood than for systolic failure. Diastole consists of two filling waves, early and late and is primarily dependent on ventricular relaxation and wall stiffness.

Nghiên cứu đánh giá chức năng tâm trương thất trái theo khuyến cáo ASE/EACVI 2016 ở bệnh nhân bệnh cơ tim giãn

2021 ◽  
Author(s):  
Quang Tuan Pham
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Left Ventricular Diastolic Function ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Ventricular Diastolic Function ◽  
Ventricular Diastolic Dysfunction ◽  
The Mean

TÓM TẮT Mục tiêu: Khảo sát chức năng tâm trương thất trái theo khuyến cáo ASE/EACVI 2016 ở bệnh nhân bệnh cơ tim giãn bằng siêu âm tim. Tìm hiểu mối liên quan giữa chức năng tâm trương thất trái với tình trạng giãn thất trái, độ suy tim NYHA, phân suất tống máu thất trái, phân suất co cơ thất trái. Đối tượng và phương pháp nghiên cứu: Nghiên cứu mô tả cắt ngang trên 56 bệnh nhân bệnh cơ tim giãn nguyên phát được nhập viện và điều trị tại bệnh viện Trung ương Huế từ tháng 4/2018 đến tháng 8/2020. Kết quả: Đường kính thất trái cuối tâm trương và cuối tâm thu trung bình là 66,11 ± 7,3 mm và 57,7 ± 8,02 mm. Đường kính nhĩ trái trung bình là 40,61 ± 7,65 mm. Phân suất tống máu thất trái trung bình là 24,68 ± 5,97 %. Phân suất co cơ thất trái trung bình là 12,91 ± 4,55 %. Tất cả các bệnh nhân nhóm nghiên cứu đều có rối loạn chức năng tâm trương thất trái. Chiếm tỷ lệ cao nhất là rối loạn chức năng tâm trương độ II (44,6%), tiếp sau là rối loạn chức năng tâm trương độ III (35,8%) và rối loạn chức năng tâm trương độ I là 19,6%. Không có sự liên quan có ý nghĩa thống kê giữa mức độ rối loạn tâm trương thất trái với đường kính thất trái cuối thì tâm thu và tâm trương (p > 0,05). Có mối liên quan giữa rối loạn chức năng tâm trương thất trái với các thông số phân suất tống máu EF và phân suất co cơ FS (p < 0,005). Có sự tương quan thuận mức độ vừa giữa phân độ rối loạn chức năng tâm trương thất trái với phân độ suy tim theo NYHA với r = 0,445, sự tương quan đó có ý nghĩa thống kê (p < 0,001). Kết luận: Tất cả các bệnh nhân bệnh cơ tim giãn trong nhóm nghiên cứu đều có rối loạn chức năng tâm trương thất trái, chủ yếu là rối loạn chức năng tâm trương nặng độ II - III. Sự rối loạn này thể hiện rõ qua sự biến đổi các thông số đánh giá chức năng tâm trương thất trái trên siêu âm tim theo khuyến cáo ASE/ EACVI 2016, một khuyến cáo mới đưa ra nhằm tiếp cận đánh giá chức năng tâm trương một cách thuận tiện và dễ dàng hơn. Từ khóa: Bệnh cơ tim giãn, rối loạn chức năng tâm trương thất trái, khuyến cáo ASE/EACVI 2016 ABSTRACT EVALUATION OF LEFT DYSTOLIC FUNCTION ACCORDING TO THE RECOMMENDATION ASE/EACVI 2016 INPATIENTS WITH DILATED CARDIOMYPAHTIES Background: Dilated cardiomyopathy is a disease of the heart muscle, characterized by dilatation of the heart chamber and a dysfunction of the left or both ventricles. It often leads to progressive heart failure, and is the leading cause of heart transplant among all cardiomyopathy. The annual rate of sudden cardiac death in dilated cardiomyopathy is 2 - 4%, with sudden death accounting for half of all deaths [9]. Echocardiography is an evaluation of a patient with dilated cardiomyopathy. There have been many studies on dilated cardiomyopathy in the world. However, there are still few studies evaluating diastolic function in patients with dilated cardiomyopathy using cardiac Doppler echocardiography. Experts around the world have made many recommendations in assessing left ventricular diastolic function, most recently is the recommendation ASE/EACVI 2016. Comparing with the 2009 EAE/ASE recommendation, the recommendation ASE/EACVI 2016 for assessment of left ventricular diastolic function has fewer parameters, so it is easier to implement and more convenient in clinical practice. Objective: Surveying left ventricular diastolic function according to the recommendation ASE/EACVI 2016 in patients with dilated cardiomyopathy by echocardiography and investigating the relationship between left ventricular diastolic function with left ventricular dilatation, heart failure NYHA, left ventricular ejection fraction, left ventricle fractional shortening. Methods: Research was designed as a cross - sectional descriptive study. Studied on 56 patients with primary dilated cardiomyopathy were hospitalized and treated at Hue Central Hospital. Results: The results showed: The mean end - diastolic and end - systolic left ventricular diameters were 66,11 ± 7,3 mm and 57,7 ± 8,02 mm. The mean left atrial diameter was 40,61 ± 7,65 mm. The mean left ventricular ejection fraction was 24,68 ± 5,97%. The mean fractional shortening of left ventricular contraction was 12,91 ± 4,55%. All patients in the study group had left ventricular diastolic dysfunction. The highest proportion is diastolic dysfunction grade II (44,6%), followed by diastolic dysfunction grade III (35,8%) and diastolic dysfunction grade I is 19,6%. There was no statistically significant relationship between the classification of left ventricular diastolic dysfunction and left ventricular systolic and diastolic diameter (p > 0.05). There is a relationship between left ventricular diastolic dysfunction and parameters of ejection fraction EF and contraction fraction FS (p < 0.005). There is a moderate positive correlation between the classification of left ventricular diastolic dysfunction and the heart failure rating according to NYHA (r = 0,445, p < 0,001). Conclusion: All patients in the study group had left ventricular diastolic dysfunction, mostly grade II and grade III diastolic dysfunction. This disorder is clearly demonstrated by the change in the parameters of the left ventricular diastolic function assessment on echocardiography according to the 2016 ASE/ EACVI recommendations, a new recommendation introduced to approach the assessment of diastolic functionmore convenient and easier way. Key words: Dilated cardiomyopathy, left ventricular diastolic dysfunction, the recommendation ASE / EACVI 2016.

scholarly journals Opportunistic screening models for high-risk men and women to detect diastolic dysfunction and heart failure with preserved ejection fraction in the community

2018 ◽  
Vol 26 (6) ◽  
pp. 613-623 ◽  
Author(s):  
Aisha Gohar ◽  
Rogier F Kievit ◽  
Gideon B Valstar ◽  
Arno W Hoes ◽  
Evelien E Van Riet ◽  
...  
Keyword(s):  
Heart Failure ◽  
High Risk ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Preserved Ejection Fraction ◽  
Men And Women ◽  
Ventricular Diastolic Dysfunction

Background The prevalence of undetected left ventricular diastolic dysfunction is high, especially in the elderly with comorbidities. Left ventricular diastolic dysfunction is a prognostic indicator of heart failure, in particularly of heart failure with preserved ejection fraction and of future cardiovascular and all-cause mortality. Therefore we aimed to develop sex-specific diagnostic models to enable the early identification of men and women at high-risk of left ventricular diastolic dysfunction with or without symptoms of heart failure who require more aggressive preventative strategies. Design Individual patient data from four primary care heart failure-screening studies were analysed (1371 participants, excluding patients classified as heart failure and left ventricular ejection fraction <50%). Methods Eleven candidate predictors were entered into logistic regression models to be associated with the presence of left ventricular diastolic dysfunction/heart failure with preserved ejection fraction in men and women separately. Internal-external cross-validation was performed to develop and validate the models. Results Increased age and β-blocker therapy remained as predictors in both the models for men and women. The model for men additionally consisted of increased body mass index, moderate to severe shortness of breath, increased pulse pressure and history of ischaemic heart disease. The models performed moderately and similarly well in men (c-statistics range 0.60–0.75) and women (c-statistics range 0.51–0.76) and the performance improved significantly following the addition of N-terminal pro b-type natriuretic peptide (c-statistics range 0.61–0.80 in women and 0.68–0.80 in men). Conclusions We provide an easy-to-use screening tool for use in the community, which can improve the early detection of left ventricular diastolic dysfunction/heart failure with preserved ejection fraction in high-risk men and women and optimise tailoring of preventive interventions.

scholarly journals Preload-corrected dynamic Starling mechanism in patients with heart failure with preserved ejection fraction

2018 ◽  
Vol 124 (1) ◽  
pp. 76-82 ◽  
Author(s):  
Michinari Hieda ◽  
Erin Howden ◽  
Shigeki Shibata ◽  
Takashi Tarumi ◽  
Justin Lawley ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Diastolic Pressure ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Preserved Ejection Fraction ◽  
Dynamic Modulation ◽  
Power Spectral ◽  
Ventricular Diastolic Dysfunction

The beat-to-beat dynamic Starling mechanism (DSM), the dynamic modulation of stroke volume (SV) because of breath-by-breath changes in left-ventricular end-diastolic pressure (LVEDP), reflects ventricular-arterial coupling. The purpose of this study was to test whether the LVEDP-SV relationship remained impaired in heart failure with preserved ejection fraction (HFpEF) patients after normalization of LVEDP. Right heart catheterization and model-flow analysis of the arterial pressure waveform were performed while preload was manipulated using lower-body negative pressure to alter LVEDP. The DSM was compared at similar levels of LVEDP between HFpEF patients ( n = 10) and age-matched healthy controls ( n = 12) (HFpEF vs. controls: 10.9 ± 3.8 vs. 11.2 ± 1.3 mmHg, P = 1.00). Transfer function analysis between diastolic pulmonary artery pressure (PAD) representing dynamic changes in LVEDP vs. SV index was applied to obtain gain and coherence of the DSM. The DSM gain was significantly lower in HFpEF patients than in the controls, even at a similar level of LVEDP (0.46 ± 0.19 vs. 0.99 ± 0.39 ml·m−2·mmHg−1, P = 0.0018). Moreover, the power spectral density of PAD, the input variability, was greater in the HFpEF group than the controls (0.75 ± 0.38 vs. 0.28 ± 0.26 mmHg2, P = 0.01). Conversely, the power spectral density of SV index, the output variability, was not different between the groups ( P = 0.97). There was no difference in the coherence, which confirms the reliability of the linear transfer function between the two groups (0.71 ± 0.13 vs. 0.77 ± 0.19, P = 0.87). The DSM gain in HFpEF patients is impaired compared with age-matched controls even at a similar level of LVEDP, which may reflect intrinsic LV diastolic dysfunction and incompetence of ventricular-arterial coupling. NEW & NOTEWORTHY The beat-to-beat dynamic Starling mechanism (DSM), the dynamic modulation of stroke volume because of breath-by-breath changes in left-ventricular end-diastolic pressure (LVEDP), reflects ventricular-arterial coupling. Although the DSM gain is impaired in heart failure with preserved ejection fraction (HFpEF) patients, it is not clear whether this is because of higher LVEDP or left-ventricular diastolic dysfunction. The DSM gain in HFpEF patients is severely impaired, even at a similar level of LVEDP, which may reflect intrinsic left-ventricular diastolic dysfunction.

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