P5443NOD2 knock down worsens diastolic dysfunction in murine angiotensin II-induced heart failure

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is associated with cardiac inflammatory responses, indicating a potential role of the immune system in the pathology of diastolic dysfunction. The cytoplasmatic pattern recognition receptor, nucleotide binding oligomerization domain 2 (NOD2) belongs to the innate immune system and induces among others the NLRP3 inflammasome, known to be involved in myocarditis and coronary heart disease. Purpose The aim of this study was to explore the role of NOD2 in Angiotensin II (AngII)-induced diastolic heart failure. Methods In NOD2−/− knock down and C57Bl6/j-wild type (WT) mice, diastolic dysfunction was induced by subcutaneous administration of 1.4mg/kg*day–1 AngII. Twenty-one days after first AngII administration, left ventricular (LV) function was evaluated by pressure tip catheter. Cardiac fibrosis, inflammation, and the expression of NOD2 and the NLRP3 component Apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) were determined via immunohistochemistry, real-time PCR or Western Blot. Results LV NOD2 mRNA expression was 2.3-fold (p<0.0005) and 1.9-fold (p<0.0005) lower in NOD2−/− control and NOD2−/− AngII mice compared to their respective WT littermates. In parallel, LV protein expression of the downstream NLRP3 component Apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) was 1.5-fold (p<0.05) lower in NOD2−/− AngII mice versus WT AngII mice, whereas LV protein IL-1β levels were unchanged. LV diastolic dysfunction was more pronounced in NOD2−/− AngII mice versus WT AngII mice, as displayed by a 19% (p<0.05) increased LV relaxation time and 24% (p<0.057) impaired dP/dtmin, with no changes in the ejection fraction (EF: NOD2−/− AngII 72.5%±5.4 versus WT AngII 65.6±3.5). In parallel, LV presence of CD68-positive cells was 1.8-fold (p<0.05) higher in NOD2−/− AngII compared to WT AngII mice. Concomitantly, NOD2−/− AngII mice displayed 1.3-fold (p<0.05) and 1.7-fold (p<0.05) higher LV mRNA expression of the chemokine macrophage inflammatory protein (MIP)-2 and monocyte chemotactant protein (MCP)-1 compared to WT AngII mice, respectively. Furthermore, cardiac interstitial fibrosis in NOD2−/− mice with AngII-induced diastolic dysperformance was more pronounced versus the WT AngII group, as indicated by a 2.0-fold (p<0.0005), 2.0-fold, and 1.6-fold (p<0.05) higher LV ColI/ColIII ratio, and TGF-β and TIMP-1 mRNA expression, respectively. Conclusion NOD2−/− deteriorates LV diastolic dysfunction and worsens pathophysiological key mechanisms in mice with AngII-induced diastolic heart failure.

Download Full-text

Sickle cell disease: at the crossroads of pulmonary hypertension and diastolic heart failure

Heart ◽

10.1136/heartjnl-2019-314810 ◽

2019 ◽

Vol 106 (8) ◽

pp. 562-568 ◽

Cited By ~ 1

Author(s):

Katherine C Wood ◽

Mark T Gladwin ◽

Adam C Straub

Keyword(s):

Heart Failure ◽

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Ejection Fraction ◽

Diastolic Dysfunction ◽

Sickle Cell ◽

Diastolic Heart Failure ◽

Left Ventricular ◽

Cell Disease ◽

Lv Diastolic Dysfunction

Sickle cell disease (SCD) is caused by a single point mutation in the gene that codes for beta globin synthesis, causing haemoglobin polymerisation, red blood cell stiffening and haemolysis under low oxygen and pH conditions. Downstream effects include widespread vasculopathy due to recurring vaso-occlusive events and haemolytic anaemia, affecting all organ systems. Cardiopulmonary complications are the leading cause of death in patients with SCD, primarily resulting from diastolic heart failure (HF) and/or pulmonary hypertension (PH). HF in SCD often features biventricular cardiac hypertrophy and left ventricular (LV) diastolic dysfunction. Among HF cases in the general population, approximately half occur with preserved ejection fraction (HFpEF). The insidious evolution of HFpEF differs from the relatively acute evolution of HF with reduced ejection fraction. The PH of SCD has diverse origins, which can be pulmonary arterial (precapillary), pulmonary venous (postcapillary) or pulmonary thromboembolic. It is also appreciated that patients with SCD can develop both precapillary and postcapillary PH, with elevations in LV diastolic pressures, as well as elevations in transpulmonary pressure gradient and pulmonary vascular resistance. Regardless of the cause of PH in SCD, its presence significantly reduces functional capacity and increases mortality. PH that occurs in the presence of HFpEF is usually of postcapillary origin. This review aims to assemble what has been learnt from clinical and animal studies about the manifestation of PH-HFpEF in SCD, specifically the contributions of LV diastolic dysfunction and myocardial fibrosis, in an attempt to gain an understanding of its evolution.

Download Full-text

Severity of LV diastolic dysfunction in patients with atrial fibrillation chronic heart failure and normal LV ejection fraction

European Journal of Heart Failure Supplements ◽

10.1016/s1567-4215(08)60367-7 ◽

2008 ◽

Vol 7 ◽

pp. 131-131

Author(s):

A OVCHINNIKOV ◽

O SVIRIDA ◽

F AGEEV

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Chronic Heart Failure ◽

Ejection Fraction ◽

Diastolic Dysfunction ◽

Lv Ejection Fraction ◽

Lv Diastolic Dysfunction

Download Full-text

Using A 21-Year Real-World Database from a Private Cardiologist's Practice to Test the Hypothesis that Combining Pharmacological Therapies (Carvedilol, Spironolactone and Statins) with Weight Loss May Benefit Patients with HFpEF

Journal of Cardiology Research ◽

10.36879/jcr.20.000133 ◽

2020 ◽

pp. 1-9

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Weight Loss ◽

Clinical Trials ◽

Endothelial Dysfunction ◽

Combination Therapy ◽

Ejection Fraction ◽

Diastolic Dysfunction ◽

Left Ventricular ◽

Lv Diastolic Dysfunction

Heart Failure with preserved Ejection Fraction (HFpEF) is a clinical syndrome in which patients have symptoms of Heart Failure (HF), such as dyspnea and fatigue, a Left Ventricular Ejection Fraction (LVEF) ≥ 50% and evidence of cardiac dysfunction as a cause of symptoms, such as abnormal Left Ventricular (LV) diastolic dysfunction with elevated filling pressures. Besides LV diastolic dysfunction, recent investigations suggest a more complex and heterogeneous pathophysiology, including systolic reserve abnormalities, chronotropic incompetence, stiffening of ventricular tissue, atrial dysfunction, secondary Pulmonary Arterial Hypertension (PAH), impaired vasodilatation and endothelial dysfunction. Unlike Heart Failure with Reduced Ejection Fraction (HFrEF), clinical trials over the years have not yet identified effective treatments that reduce mortality in patients with HFpEF. A database on use of carvedilol in a private cardiologist's practice was begun in 1997 and concluded at the end of 2018. We used this database to test the hypothesis that combining pharmacological interventions to address diastolic dysfunction (carvedilol), volume overload (spironolactone/eplerenone) and endothelial dysfunction (statins) with weight loss may benefit patients with HFpEF. We report analysis of 335 patients with HFpEF comprised of 61% female (mean age 74 ± 8) and 39% males (mean age 72 ± 7). Initial EF ranged between 50 and 77% with mean EF of 57 ± 6%. Only 15 patients were changed to metoprolol succinate, verapamil or diltiazem because of adverse side effects. Two hundred and twenty of the patients were in normal sinus rhythm when started on carvedilol, spironolactone/eplerenone and statin therapy with weight loss counseling. After 5 years, 191 patients were still on combination therapy, and only 31 (17%) had developed Atrial Fibrillation (AF). Compared to previous HFpEF trials reporting a 32% risk of developing atrial fibrillation after 4 years, our combination therapy significantly (p < 0.05) reduced the risk of developing AF over 5 years. Thus, irrespective of age and sex with comorbidities of type 2 Diabetes Mellitus (DM) and Chronic Kidney Disease (CKD), patients with HFpEF can be managed successfully with carvedilol, spironolactone/eplerenone and statins with a clinical benefit being a reduced risk of developing AF. We consider these data hypothesis-generating and hope these results will be tested further in database analyses and clinical trials.

Download Full-text

UCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II‐Induced Hypertension

Journal of the American Heart Association ◽

10.1161/jaha.121.022556 ◽

2021 ◽

Vol 10 (18) ◽

Author(s):

Xu Chen ◽

Sadia Ashraf ◽

Nadia Ashraf ◽

Romain Harmancey

Keyword(s):

Heart Failure ◽

Angiotensin Ii ◽

Ejection Fraction ◽

Diastolic Dysfunction ◽

Uncoupling Protein ◽

Left Ventricular Diastolic Dysfunction ◽

Left Ventricular ◽

Preserved Ejection Fraction ◽

Uncoupling Protein 3 ◽

Ventricular Diastolic Dysfunction

Background Left ventricular diastolic dysfunction, an early stage in the pathogenesis of heart failure with preserved ejection fraction, is exacerbated by joint exposure to hypertension and obesity; however, the molecular mechanisms involved remain uncertain. The mitochondrial UCP3 (uncoupling protein 3) is downregulated in the heart with obesity. Here, we used a rat model of UCP3 haploinsufficiency (ucp3 +/‐ ) to test the hypothesis that decreased UCP3 promotes left ventricular diastolic dysfunction during hypertension. Methods and Results Ucp3 +/‐ rats and ucp3 +/+ littermates fed a high‐salt diet (HS; 2% NaCl) and treated with angiotensin II (190 ng/kg per min for 28 days) experienced a similar rise in blood pressure (158±4 versus 155±7 mm Hg). However, UCP3 insufficiency worsened diastolic dysfunction according to echocardiographic assessment of left ventricular filling pressures (E/e’; 18.8±1.0 versus 14.9±0.6; P <0.05) and the isovolumic relaxation time (24.7±0.6 versus 21.3±0.5 ms; P <0.05), as well as invasive monitoring of the diastolic time constant (Tau; 15.5±0.8 versus 12.7±0.2 ms; P <0.05). Exercise tolerance on a treadmill also decreased for HS/angiotensin II‐treated ucp3 +/‐ rats. Histological and molecular analyses further revealed that UCP3 insufficiency accelerated left ventricular concentric remodeling, detrimental interstitial matrix remodeling, and fetal gene reprogramming during hypertension. Moreover, UCP3 insufficiency increased oxidative stress and led to greater impairment of protein kinase G signaling. Conclusions Our findings identified UCP3 insufficiency as a cause for increased incidence of left ventricular diastolic dysfunction during hypertension. The results add further support to the use of antioxidants targeting mitochondrial reactive oxygen species as an adjuvant therapy for preventing heart failure with preserved ejection fraction in individuals with obesity.

Download Full-text

P3789Circulating biomarkers of myocardial fibrosis and cellular apoptosis in patients with atrial fibrillation and heart failure with preserved ejection fraction

European Heart Journal ◽

10.1093/eurheartj/ehz745.0635 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

M S Dzeshka ◽

E Shantsila ◽

V A Snezhitskiy ◽

G Y H Lip

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Angiotensin Ii ◽

Ejection Fraction ◽

Matrix Metalloproteinase ◽

Diastolic Dysfunction ◽

Diastolic Function ◽

Myocardial Fibrosis ◽

Volume Index ◽

Preserved Ejection Fraction

Abstract Introduction Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) commonly coexist. AF is associated with left atrial (LA) and ventricular (LV) myocardial fibrosis, contributing to diastolic dysfunction in HFpEF. Many profibrotic pathways have been studied in AF and HFpEF, but scarce data are available on the role of circulating microparticles (MPs). Purpose To evaluate association of circulating biomarkers of fibrosis and MPs subsets with Doppler-derived parameters of diastolic function in AF and HFpEF. Methods We studied 274 patients with non-valvular AF and HFpEF (median age 62 years, 37% females). Paroxysmal AF was diagnosed in 150 patients (55%) and non-paroxysmal AF (persistent or permanent) in 124 (45%). Median CHA2DS2-VASc score was 3 in males and 4 in females. Transthoracic echocardiography was performed to assess LV diastolic function, including early mitral inflow velocity (E), E/A velocities ratio (on sinus rhythm), early mitral annular diastolic velocity (E') for LV septal and lateral basal regions, E/E' ratio, LA maximum volume index (LAVi), E-wave velocity deceleration time (DT), flow propagation velocity (Vp). Average values from ten consecutive cardiac cycles were calculated. E/E' ratio was chosen as valid and reproducible index of diastolic function in AF patients for regression analysis. Blood levels of galectin 3, interleukin-1 receptor-like 1 (ST2), transforming growth factor beta 1 (TGF-β1), procollagen type III aminoterminal propeptide (PIIINP), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), angiotensin II and aldosterone level were assayed as surrogate biomarkers of myocardial fibrosis and profibrotic signaling. Using microflow cytometry, numbers of platelet-derived (CD42b+), monocyte-derived (CD14+), endothelial (CD144+), and apoptotic MPs (Annexin V+) were quantified in plasma samples. Linear regression was used to reveal parameters associated with diastolic function assessed as E/E' ratio. Data were normalized with Box-Cox transformation. Results Grade I diastolic dysfunction was found in 149 (54%); 94 (34%), and 31 (11%) patients had grade II and grade III diastolic dysfunction, respectively. On univariate analysis, age (β=0.23, p=0.0001); male gender (β=-0.19, p=0.02); history of hypertension (β=0.15, p=0.02); AF type, i.e. progression from paroxysmal to permanent (β=0.14, p=0.02); AnV+ MPs (β=0.19, p=0.01); angiotensin II (β=0.13, p=0.04); ST2 (β=0.1, p=0.04); and TIMP-1 (β=0.13, p=0.03) were associated with E/E' ratio. Using stepwise multivariate regression, AnV+ MPs (β=0.15, p=0.01) and TIMP-1 (β=0.3, p=0.04) remained significant predictors of E/E' ratio, adjusted for age, gender, hypertension and AF type. Relation of E/E' to TIMP-1 and AnV+ MPs Conclusion Apoptotic (AnV+) MPs and TIMP-1 were independently associated with diastolic dysfunction in AF and HFpEF. These may contribute to the pathophysiology of AF and HFpEF, and complications related to the presence of both. Acknowledgement/Funding ESC Research Grant, EHRA Academic Research Fellowship Programme

Download Full-text

Link between diabetes and diastolic dysfunction and the diagnostic role of echocardiography

Orvosi Hetilap ◽

10.1556/oh.2009.28738 ◽

2009 ◽

Vol 150 (45) ◽

pp. 2060-2067 ◽

Cited By ~ 1

Author(s):

András Nagy ◽

Zsuzsanna Cserép

Keyword(s):

Heart Failure ◽

Diastolic Dysfunction ◽

Systolic Function ◽

Diastolic Heart Failure ◽

Systolic Dysfunction ◽

Mitral Annulus ◽

Left Ventricular ◽

Diabetic Patients ◽

Doppler Study

Diabetes mellitus, a disease that has been reaching epidemic proportions, is an important risk factor to the development of cardiovascular complication. The left ventricular diastolic dysfunction represents the earliest pre-clinical manifestation of diabetic cardiomyopathy, preceding systolic dysfunction and being able to evolve to symptomatic heart failure. In early stages, these changes appear reversible with tight metabolic control, but as pathologic processes become organized, the changes are irreversible and contribute to an excess risk of heart failure among diabetic patients. Doppler echocardiography provides reliable data in the stages of diastolic function, as well as for systolic function. Combination of pulsed tissue Doppler study of mitral annulus with transmitral inflow may be clinically valuable for obtaining information about left ventricular filling pressure and unmasking Doppler inflow pseudonormal pattern, a hinge point for the progression toward advanced heart failure. Subsequently we give an overview about diabetes and its complications, their clinical relevance and the role of echocardiography in detection of diastolic heart failure in diabetes.

Download Full-text

Abstract P490: Vascular Rarefaction And Decreased Angiogenic Potential In The Development Of Left Ventricular Diastolic Dysfunction In Heart Failure With Preserved Ejection Fraction

Circulation Research ◽

10.1161/res.129.suppl_1.p490 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Katie Anne Fopiano ◽

Yanna Tian ◽

Vadym Buncha ◽

Liwei Lang ◽

Zsolt Bagi

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Diastolic Dysfunction ◽

Rat Model ◽

Ex Vivo ◽

Diastolic Heart Failure ◽

Left Ventricular ◽

Coronary Microvascular Dysfunction ◽

Preserved Ejection Fraction ◽

Angiogenic Potential

Coronary microvascular dysfunction (CMD) develops in patients with heart failure with preserved ejection fraction (HFpEF, also known as diastolic heart failure), but the nature of the underlying pathomechanisms behind this prevalent disease remain poorly understood. The hypothesis tested was that coronary microvascular rarefaction contributes to left ventricle (LV) diastolic function in HFpEF. The obese ZSF1 rat model of human HFpEF was employed and using transthoracic echocardiography it was found that 18-week-old male obese ZSF1 rats exhibited a significantly reduced E/A ratio (E=early, A=late mitral inflow peak velocities) and increased DT (E wave deceleration time) with no change in ejection fraction, indicating diastolic dysfunction. Coronary arteriolar and capillary trees were labeled using Tomato Lectin (Lycopersicon esculentum) DyLight®594 and were imaged by fluorescent confocal microscopy to generate image stacks for 3D reconstruction. Unbiased automated tracing of the microvasculature was done using VesselLucida360 software (MBF) followed by a morphometric analysis (VesselLucida Explorer). It was found that total vessel length and the number of vessel’s branching nodes were reduced in the obese ZSF1 rats, whereas the total vessel’s volumes remained consistent, when compared to the lean ZSF1 controls. These changes in the microvasculature were accompanied by decreased angiogenesis in the coronary arteries in the obese ZSF1 rats when compared to the lean ZSF1 rats using an ex vivo endothelial sprouting assay. From these results, it was concluded that vascular rarefaction and decreased angiogenesis both play a role in the development of LV diastolic dysfunction in the obese ZSF1 rat model of human HFpEF.

Download Full-text

Abstract 11217: A New Treatment for Diastolic Heart Failure: Trabecular Cutting

Circulation ◽

10.1161/circ.130.suppl_2.11217 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

David L Halaney ◽

Pedro J Acevedo ◽

William Pérez ◽

Marc D Feldman

Keyword(s):

Heart Failure ◽

Diastolic Dysfunction ◽

Ex Vivo ◽

Diastolic Heart Failure ◽

Wall Stress ◽

Mitral Annulus ◽

Cardiac Titin ◽

Before And After ◽

Diastolic Compliance ◽

Lv Diastolic Dysfunction

Background: Heart failure with preserved ejection fraction remains a leading cause of hospitalization, without development of new medications and operative procedures to treat these patients. We hypothesize that trabeculae carneae serve an important role in modulating LV diastolic compliance, and during hypertrophy of the myocardium, trabeculae contribute to abnormal compliance. Methods and Results: Eight ex vivo human hearts from patients with LV diastolic dysfunction were perfused at 37[[Unable to Display Character: ⁰]]C and had a balloon inserted into the LV through the mitral annulus. Diastolic LV pressure-volume compliance curves were measured at baseline and following trabecular cutting. LV compliance improved significantly (n=6, p<0.001), but not in the control hearts without trabecular cutting (n=2, p=0.85). The figure shows aggregate data from the six hearts before and after trabecular cutting. To determine if trabeculae serve a similar role in all mammals, 28 hearts from 10 species were obtained. We demonstrate significant relationships between circumferential wall stress and the number of trabeculae in these species, particularly trabeculae which attach nets of trabeculae to the ventricle walls (p=0.02, n=733) and trabeculae located at the apex and free wall (p=0.02, n=602). The percent of LV cardiac titin of the stiff isoform (%N2B), a determinate of LV diastolic compliance, also demonstrated a significant relationship with the number of trabeculae with the same anatomic subsets (p=0.04, n=597; and p=0.02, n=488, respectively). Conclusions: We demonstrate for the first time that rather than being an embryologic remnant, trabeculae carneae serve an important role in the maintenance of passive LV diastolic compliance, and can contribute to LV diastolic dysfunction. A new procedure, cutting trabeculae, is proposed to improve LV diastolic compliance.

Download Full-text

Heart failure with preserved ejection fraction (diastolic heart failure)

Orvosi Hetilap ◽

10.1556/oh.2012.29506 ◽

2012 ◽

Vol 153 (51) ◽

pp. 2030-2040 ◽

Cited By ~ 2

Author(s):

István Czuriga ◽

Attila Borbély ◽

Dániel Czuriga ◽

Zoltán Papp ◽

István Édes

Keyword(s):

Heart Failure ◽

Heart Rate ◽

Ejection Fraction ◽

Diastolic Dysfunction ◽

Diastolic Heart Failure ◽

Left Ventricular ◽

Preserved Ejection Fraction ◽

Normal Left Ventricular ◽

Left Ventricular Dimensions ◽

Ventricular Dimensions

Diastolic heart failure, which is also called as heart failure with preserved ejection fraction, is a clinical syndrome in which patients have signs and symptoms of heart failure, normal or near normal left ventricular ejection fraction (≥50%) and evidence of diastolic dysfunction. Recent epidemiological studies have demonstrated that more than half of all heart failure patients have diastolic heart failure. The syndrome is more common in women than in men and the prevalence increases with age. Patients with diastolic heart failure form a fairly heterogeneous group with complex pathophysiologic mechanisms. The disease is often in association with other comorbidities, such as hypertension, diabetes mellitus or obesity. The diagnosis of diastolic heart failure is best achieved by two-dimensional and Doppler echocardiography, which can detect abnormal myocardial relaxation, decreased compliance and increased filling pressure in the setting of normal left ventricular dimensions and preserved ejection fraction. Unlike heart failure with reduced ejection fraction, there is no such an evidence-based treatment for heart failure with preserved ejection fraction, which would improve clinical outcomes. Thus, pharmacological therapy of diastolic heart failure is based mainly on empiric data, and aims to the normalization of blood pressure, reduction of left ventricular dimensions and increased heart rate, maintenance of normal atrial contraction and treatment of symptoms caused by congestion. Beneficial effects of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers may be utilized in patients with diastolic dysfunction, especially in those with hypertension. Beta-blockers appear to be useful in lowering heart rate and thereby prolonging left ventricular diastolic filling time, while diuretic therapy is the mainstay of treatment for preventing pulmonary congestion. Nonetheless, treatment of the underlying disease is also an important therapeutic approach. This review summarizes the state of current knowledge with regard to diastolic heart failure. Orv. Hetil., 2012, 153, 2030–2040.

Download Full-text