scholarly journals Arrhythmogenic Hearts in PKD2 Mutant Mice Are Characterized by Cardiac Fibrosis, Systolic, and Diastolic Dysfunctions

2021 ◽  
Vol 8 ◽  
Author(s):  
Farideh Amirrad ◽  
Rajasekharreddy Pala ◽  
Kiumars Shamloo ◽  
Brian S. Muntean ◽  
Surya M. Nauli
Keyword(s):  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Stress Test ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Mouse Heart ◽  
Wild Type ◽  
Pharmacological Stress ◽  
Functional Changes

Autosomal dominant polycystic kidney disease (PKD) is a hereditary disorder affecting multiple organs, including the heart. PKD has been associated with many cardiac abnormalities including the arrhythmogenic remodeling in clinical evaluations. In our current study, we hypothesized that Pkd2 gene mutation results in structural and functional defects in the myocardium. The structural and functional changes of Pkd2 mutant hearts were analyzed in the myocardial-specific Pkd2 knockout (KO) mouse. We further assessed a potential role of TGF-b1 signaling in the pathology of Pkd2-KO hearts. Hearts from age-matched 6-month-old MyH6•Pkd2wt/wt (control or wild-type) and MyH6•Pkd2flox/flox (mutant or Pkd2-KO) mice were used to study differential heart structure and function. Cardiac histology was used to study structure, and the “isolated working heart” system was adapted to mount and perfuse mouse heart to measure different cardiac parameters. We found that macrophage1 (M1) and macrophage 2 (M2) infiltration, transforming growth factor (TGF-b1) and TGF-b1 receptor expressions were significantly higher in Pkd2-KO, compared to wild-type hearts. The increase in the extracellular matrix in Pkd2-KO myocardium led to cardiac hypertrophy, interstitial and conduction system fibrosis, causing cardiac dysfunction with a predisposition to arrhythmia. Left ventricular (LV) expansion or compliance and LV filling were impaired in fibrotic Pkd2-KO hearts, resulted in diastolic dysfunction. LV systolic contractility and elastance decreased in fibrotic Pkd2-KO hearts, resulted in systolic dysfunction. Compared to wild-type hearts, Pkd2-KO hearts were less responsive to the pharmacological stress-test and changes in preload. In conclusion, Pkd2-KO mice had systolic and diastolic dysfunction with arrhythmogenic hearts.

scholarly journals Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload

Cardiology ◽  
2020 ◽  
Vol 145 (3) ◽  
pp. 187-198 ◽  
Author(s):  
Naiyereh Mohammadzadeh ◽  
Arne Olav Melleby ◽  
Sheryl Palmero ◽  
Ivar Sjaastad ◽  
Shukti Chakravarti ◽  
...  
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cross Linking ◽  
Myocardial Remodeling ◽  
Functional Changes ◽  
Collagen Cross Linking

Introduction: The heart undergoes myocardial remodeling during progression to heart failure following pressure overload. Myocardial remodeling is associated with structural and functional changes in cardiac myocytes, fibroblasts, and the extracellular matrix (ECM) and is accompanied by inflammation. Cardiac fibrosis, the accumulation of ECM molecules including collagens and collagen cross-linking, contributes both to impaired systolic and diastolic function. Insufficient mechanistic insight into what regulates cardiac fibrosis during pathological conditions has hampered therapeutic so­lutions. Lumican (LUM) is an ECM-secreted proteoglycan known to regulate collagen fibrillogenesis. Its expression in the heart is increased in clinical and experimental heart failure. Furthermore, LUM is important for survival and cardiac remodeling following pressure overload. We have recently reported that total lack of LUM increased mortality and left ventricular dilatation, and reduced collagen expression and cross-linking in LUM knockout mice after aortic banding (AB). Here, we examined the effect of LUM on myocardial remodeling and function following pressure overload in a less extreme mouse model, where cardiac LUM level was reduced to 50% (i.e., moderate loss of LUM). Methods and Results: mRNA and protein levels of LUM were reduced to 50% in heterozygous LUM (LUM+/–) hearts compared to wild-type (WT) controls. LUM+/– mice were subjected to AB. There was no difference in survival between LUM+/– and WT mice post-AB. Echocardiography revealed no striking differences in cardiac geometry between LUM+/– and WT mice 2, 4, and 6 weeks post-AB, although markers of diastolic dysfunction indicated better function in LUM+/– mice. LUM+/– hearts revealed reduced cardiac fibrosis assessed by histology. In accordance, the expression of collagen I and III, the main fibrillar collagens in the heart, and other ECM molecules central to fibrosis, i.e. including periostin and fibronectin, was reduced in the hearts of LUM+/– compared to WT 6 weeks post-AB. We found no differences in collagen cross-linking between LUM+/– and WT mice post-AB, as assessed by histology and qPCR. Conclusions: Moderate lack of LUM attenuated cardiac fibrosis and improved diastolic dysfunction following pressure overload in mice, adding to the growing body of evidence suggesting that LUM is a central profibrotic molecule in the heart that could serve as a potential therapeutic target.

Abstract 78: Transforming Growth Factor-β Induces the Cardiac Fibrosis and Remodeling in Guanylyl cyclase/Natriuretic Peptide Receptor-A Gene-Disrupted Null Mutant Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Kailash N Pandey ◽  
Umadevi Subramanian
Keyword(s):  
Growth Factor ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Left Ventricular ◽  
Null Mutant ◽  
Wild Type ◽  
Peptide Receptor ◽  
Natriuretic Peptide Receptor A ◽  
Β Receptor ◽  
Null Mutant Mice

Genetic disruption of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene (Npr1) in mice exhibits high blood pressure, cardiac hypertrophy, fibrosis, and remodeling leading to congestive heart failure. The objective of this study was to determine the mechanisms regulating the development of fibrosis in Npr1 gene-disrupted mice hearts. The Npr1 null mutant (Npr1-/-, 0-copy), heterozygous (Npr1+/-, 1-copy), and wild-type (Npr1+/+, 2-copy) mice were administered by oral gavage with transforming growth factor-β1 (TGF- β1) receptor inhibitor GW788388 (1mg/kg/day) for 28 days. The heart tissues were isolated and used for quantification of fibrotic markers by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot analyses. Together, systolic blood pressure (SBP), heart weight-to-body weight (HW/BW) ratio, left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVEDS), and percent fractional shortening (FS) were analyzed. The Npr1-/- null mutant mice hearts displayed 6-fold induction of fibrosis compared with wild-type (WT) Npr1+/+ mice. Furthermore, the increased expression of fibrotic markers as observed, including connective tissue growth factor (CTGF, 5-fold), α-smooth muscle actin (α-SMA, 4-fold) and TGF-β receptor I (TGF-βRI, 4-fold), TGF-β receptor II (TGF-βRII, 3.5-fold) and Smad2/3 proteins in Npr1-/- mice hearts compared with WT control mice. However, treatment with TGF-β receptor antagonist, GW788388, significantly prevented the cardiac fibrosis and down-regulated the expression of fibrotic markers and Smad proteins in Npr1-/- mice compared to vehicle-treated WT controls. The results of the present study suggest that the activation of cardiac fibrosis in Npr1-/- mice is mainly triggered through TGF-β mediated Smad-dependent pathways.

Abstract 3430: Left Ventricular Hypertrophy and Diastolic Dysfunction in Mice Lacking All Nitric Oxide Synthase Isoforms

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Masato Tsutsui ◽  
Kiyoko Shibata ◽  
Hiroaki Shimokawa ◽  
Yasuko Yatera ◽  
Yumi Furuno ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Systolic Function ◽  
Left Ventricular ◽  
Functional Changes ◽  
Arterial Blood ◽  
Oxide Synthase

We have recently succeeded in developing mice in which all three nitric oxide synthase isoforms (nNOS, iNOS, and eNOS) are completely disrupted ( PNAS 2005). In this study, we examined cardiac morphology and function in those mice. Cardiac echocardiography and left ventricular (LV) hemodynamic measurement were performed in male wild-type (WT), singly nNOS −/− , iNOS −/− , eNOS −/− , and triply n/i/eNOS −/− mice at 2 and 5 months of age (n=5–8). At 2 months of age, no significant cardiac morphological or functional changes were detected in any strains studied. However, at 5 months of age, significant LV hypertrophy (wall thickness, mm) were noted in the triply n/i/eNOS −/− mice (1.3±0.1, P <0.01) and to a lesser extent in the singly eNOS −/− mice (1.1±0.1, P <0.05), but not in the singly nNOS −/− (0.8±0.1) or iNOS −/− mice (1.0±0.1), as compared with the WT mice (1.0±0.2). Furthermore, significant LV diastolic dysfunction (as evaluated by echocardiographic E/A ratio and by hemodynamic peak negative dP/dt), with preserved LV systolic function (as assessed by echocardiographic ejection fraction and by hemodynamic peak positive dP/dt), was noted only in the 5-month-old triply n/i/eNOS −/− mice (2.7±0.1 and 2505±60, both P <0.05), but not in any singly nNOS −/− (2.1±0.2 and 3833±402), iNOS −/− (2.0±0.1 and 3773±747), or eNOS −/− mice (2.0±0.3 and 2934±122), as compared with the WT mice (1.9±0.1 and 4038±344). In addition, significant cardiac fibrosis (fibrosis area, %, Masson-trichrome staining) was also detected only in the 5-month-old triply n/i/eNOS −/− mice (1.4±0.2, P <0.05) compared with the WT mice (0.3±0.1). Importantly, arterial blood pressure (mmHg, tail-cuff method) was significantly elevated in the triply n/i/eNOS −/− (143±3.1, P <0.05) than in the WT mice (104±7.3), but the hypertensive level was comparable to that in the singly eNOS −/− mice (140±8.5). Thus, mechanism(s) other than hypertension appears to be involved in the cardiac abnormalities of the triply n/i/eNOS −/− mice. These results provide the first evidence that genetic disruption of all NOSs results in LV hypertrophy and diastolic dysfunction in mice in vivo, suggesting a pivotal role of the NOS system in maintaining cardiac homeostasis.

scholarly journals The α11 integrin mediates fibroblast–extracellular matrix–cardiomyocyte interactions in health and disease

2016 ◽  
Vol 311 (1) ◽  
pp. H96-H106 ◽  
Author(s):  
Robert A. Civitarese ◽  
Ilana Talior-Volodarsky ◽  
Jean-Francois Desjardins ◽  
Golam Kabir ◽  
Jennifer Switzer ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Connexin 43 ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Diastolic Pressure ◽  
Interstitial Fibrosis ◽  
Mouse Heart ◽  
Wild Type ◽  
The Impact

Excessive cardiac interstitial fibrosis impairs normal cardiac function. We have shown that the α11β1 (α11) integrin mediates fibrotic responses to glycated collagen in rat myocardium by a pathway involving transforming growth factor-β. Little is known of the role of the α11 integrin in the developing mammalian heart. Therefore, we examined the impact of deletion of the α11 integrin in wild-type mice and in mice treated with streptozotocin (STZ) to elucidate the role of the α11 integrin in normal cardiac homeostasis and in the pathogenesis of diabetes-related fibrosis. As anticipated, cardiac fibrosis was reduced in α11 integrin knockout mice (α11−/−; C57BL/6 background) treated with STZ compared with STZ-treated wild-type mice ( P < 0.05). Unexpectedly, diastolic function was impaired in both vehicle and STZ-treated α11−/− mice, as shown by the decreased minimum rate of pressure change and prolonged time constant of relaxation in association with increased end-diastolic pressure (all P < 0.05 compared with wild-type mice). Accordingly, we examined the phenotype of untreated α11−/− mice, which demonstrated a reduced cardiomyocyte cross-sectional cell area and myofibril thickness (all P < 0.05 compared with wild-type mice) and impaired myofibril arrangement. Immunostaining for desmin and connexin 43 showed abnormal intermediate filament organization at intercalated disks and impaired gap-junction development. Overall, deletion of the α11 integrin attenuates cardiac fibrosis in the mammalian mouse heart and reduces ECM formation as a result of diabetes. Furthermore, α11 integrin deletion impairs cardiac function and alters cardiomyocyte morphology. These findings shed further light on the poorly understood interaction between the fibroblast–cardiomyocyte and the ECM.

Abstract 14664: Reduced Activin Like Kinase 1 Activity Promotes Cardiac Fibrosis in Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Kevin Morine ◽  
Vikram Paruchuri ◽  
Xiaoying Qiao ◽  
Emily Mackey ◽  
Mark Aronovitz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Left Ventricular ◽  
Lv Function ◽  
Type I ◽  
Mrna Levels ◽  
Protein Levels

Introduction: Activin receptor like kinase 1 (ALK1) mediates signaling via transforming growth factor beta-1 (TGFb1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. Methods and Results: ALK1 mRNA expression was quantified by RT-PCR in left ventricular (LV) tissue from patients with end-stage heart failure and compared to control LV tissue obtained from the National Disease Research Interchange (n=8/group). Compared to controls, LV ALK1 mRNA levels were reduced by 85% in patients with heart failure. Next, using an siRNA approach, we tested whether reduced ALK1 levels promote TGFb1-mediated collagen production in human cardiac fibroblasts. Treatment with an ALK1 siRNA reduced ALK1 mRNA levels by 75%. Compared to control, TGFb1-mediated Type I collagen and pSmad-3 protein levels were 2.5-fold and 1.7-fold higher, respectively, after ALK1 depletion. To explore a role for ALK1 in heart failure, ALK1 haploinsufficient (ALK1) and wild-type mice (WT; n=8/group) were studied 2 weeks after thoracic aortic constriction (TAC). Compared to WT, baseline LV ALK1 mRNA levels were 50% lower in ALK1 mice. Both LV and lung weights were higher in ALK1 mice after TAC. Cardiomyocyte area and LV mRNA levels of BNP, RCAN, and b-MHC were increased similarly, while SERCa levels were reduced in both ALK1 and WT mice after TAC. Compared to WT, LV fibrosis (Figure) and Type 1 Collagen mRNA and protein levels were higher among ALK1 mice. Compared to WT, LV fractional shortening (48±12 vs 26±10%, p=0.01) and survival (Figure) were lower in ALK1 mice after TAC. Conclusions: Reduced LV expression of ALK1 is associated with advanced heart failure in humans and promotes early mortality, impaired LV function, and cardiac fibrosis in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.

Abstract 18141: Is There Systolic Myocardial Mechanical Dysfunction in Patients With Different Degrees of Diastolic Dysfunction and Normal Ejection Fraction?

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sergio Barros-Gomes ◽  
Patricia A Pellikka ◽  
Angela Dispenzieri ◽  
Hector R Villarraga
Keyword(s):  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Al Amyloidosis ◽  
Normal Ejection Fraction ◽  
Group 4 ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Introduction: Diastolic dysfunction has been characterized in relation to the relaxation and compliance properties of the left ventricle; limited information exists regarding its relationship to systolic function as assessed by deformation imaging. Objectives: To determine if there is left ventricular systolic dysfunction detected by global longitudinal strain (GLS) measured by two dimensional speckle tracking echocardiography in patients with immunoglobulin light chain (AL) amyloidosis with different degrees of diastolic dysfunction and normal ejection fraction (EF). Methods: Consecutive biopsy-proven AL patients with preserved EF (≥ 55%) who had a comprehensive echocardiogram performed and strain analysis were included. Cohort was divided into 5 groups according to the different grades of diastolic dysfunction: Group 0: normal filling pressures; Group 1: abnormal relaxation; Group 2: pseudo-normal pattern; Group 3: reversible restrictive; Group 4: fixed restrictive. Images were acquired and performed on a Vivid 9 from the 3 apical views, and analyzed on vendor-specific software (Echo-PAC, GE). GLS was averaged from the 16 segments, and their means compared by ANOVA and each pair with Student’s t test. Results: A total of 858 patients were included, mean age was 63.7 years ± 10.1, and 61.5% were male. From those, 205 (24%) were in group 0; 299 (35%) in group 1; 255 (30%) in group 2; 65 (7%) in group 3; and 34 in group 4 (4%). GLS means measurements were -18.95 ± 2.4, -16.86 ± 3.4, -15.60 ± 3.9, -12.31 ± 3.0, and -10.48 ± 3.3, respectively (P<0.0001). All individual GLS values were significantly different statistically when compared between each group (P<0.01 for all pairs; figure). Conclusions: Longitudinal systolic mechanical function is progressively impaired in AL amyloid patients as diastolic dysfunction progresses, despite normal EF. This systolic dysfunction provides insights into the intrinsic relationship between the components of the cardiac cycle.

scholarly journals Microalbuminuria as a Marker of Preclinical Diastolic Dysfunction in Newly Diagnosed and Never-Treated Essential Hypertension

2013 ◽  
Vol 35 (1) ◽  
pp. 3-8
Author(s):  
RM Gajurel ◽  
A Sayami
Keyword(s):  
Essential Hypertension ◽  
Diastolic Dysfunction ◽  
Myocardial Dysfunction ◽  
Public Health Problem ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Newly Diagnosed ◽  
Spot Urine ◽  
Functional Changes ◽  
Ventricular Diastolic Dysfunction

Introduction: Hypertension (HTN) is a global public health problem with one fourth adults worldwide estimated to have high blood pressure (BP)1 The incidence of hypertension continues to increase in all developed and developing societies as the population grows older and more obese. The Framingham Study and other epidemiological surgeys have clearly defined HTN as an important cause of morbidity and mortality. The aim of this study was to determine the spot urine Microalbuminuria as a marker of preclinical cardiac structural and functional changes in the form of left ventricular diastolic dysfunction in newly diagnosed and never treated essential hypertensive subjects. Methods: A cross sectional study was used for those patients who were attended outpatient clinic of MCVTC with diagnosis of newly diagnosed and never treated hypertension over a period of October 2011 to November 2012. Results: A total of 130 essential hypertensive patients underwent for spot urine for microalbuminuria estimation and Echocardiography for evaluation of left ventricular diastolic function. Among 56 (43.1%) urine samples showed negative test [(Microalbuminuria -); ( UACR 30 mg/Gm)] and those 74 (56.9%) samples revealed positive test [(Microalbuminuria+); (UACR 30 to 300 mg/Gm)]. Patients with microalbuminuria positive was found to have more left ventricular diastolic dysfunction than those who were negative for Microalbuminuria. Conclusion: Microalbuminuria was found to have early preclinical marker of myocardial dysfunction in the form of left ventricular diastolic dysfunction in new and never treated essential hypertension. DOI: http://dx.doi.org/10.2126/joim.v35i1.8890  Journal of Institute of Medicine, April, 2013; 35:3-8

Abstract 13910: Importance of Non-invasive Estimates of Left Ventricular Filling Pressures in Critically Ill Patients

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Abdelrahman M Ahmed ◽  
Brandon Wiley ◽  
Jacob C Jentzer ◽  
Nandan S Anavekar ◽  
Allan S Jaffe
Keyword(s):  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Troponin T ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Adverse Outcomes ◽  
Icu Mortality ◽  
Lv Diastolic Function

Introduction: The presence of cardiac dysfunction predicts adverse outcomes in the intensive care unit (ICU). We explored the relationship of cardiac injury and left ventricular (LV) systolic and diastolic dysfunction (LVDD) to outcomes in critically ill patients. Methods: This is a retrospective analysis of adult medical ICU admissions from May, 2018 through October 2019. Patients with elevated high-sensitivity troponin T (hs-cTnT) and an echocardiogram performed within 72 hours of admission were included. Patients were classified as having normal LV diastolic function, isolated LVDD, concomitant LV diastolic and systolic dysfunction (LVDDSD) or indeterminate LV diastolic function based on American Society of Echocardiography 2016 guidelines. LV systolic dysfunction was defined as an ejection fraction (EF) < 50%. Results: Overall, 222 patients were included. LVDD was seen in 123 patients (55.4%). Thirty patients (13.5%) were classified with indeterminate diastolic function and 56 normal diastolic function (25.2%). Of those with LVDD , 59.3% had LVDDSD while isolated LVDD was seen in 40.7%.Patients with LVDDSD had a higher median hs-cTnT at baseline compared to patients with isolated LVDD [102ng/L IQR (50-257) vs. 77 ng/L (33.5-166); p=0.047]. Medial e’ velocity and tricuspid valve systolic regurgitant velocity were often associated with LV systolic dysfunction (p=0.0172 and 0.0013, respectively). LVDDSD was associated with a longer length of stay than patients with isolated LVDD [2.9 (1.6-4.0) vs.1.8 (1.1-3.3); p-value 0.03].Twenty-nine patients died during their ICU stay (13%). Patients with LVDDSD had 9.6-fold higher odds of dying in the ICU than patients with isolated LVDD (p=0.0048). Reduced medial e’ velocity (OR 0.63, CI 0.4-1.0, p=0.0285) and increased E/e’ (OR 1.08, CI 1.01-1.15, p=0.0192) were associated with ICU mortality. The association between LVEF<50% and ICU mortality was less pronounced (OR 0.95, CI 0.01-0.98; p=0.0023). Conclusions: Concomitant LV systolic and diastolic dysfunction and measures of increased cardiac filling pressures are strong predictors of mortality.

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