Deletion of Microfibrillar‐Associated Protein 4 Attenuates Left Ventricular Remodeling and Dysfunction in Heart Failure

Background Cardiac remodeling predisposes individuals to heart failure if the burden is not solved, and heart failure is a growing cause of morbidity and mortality worldwide. The cardiac extracellular matrix not only provides structural support, but also is a core aspect of the myocardial response to various biomechanical stresses and heart failure. MFAP4 (microfibrillar‐associated protein 4) is an integrin ligand located in the extracellular matrix, whose biological functions in the heart remain poorly understood. In the current study we aimed to test the role of MFAP4 in cardiac remodeling. Methods and Results MFAP4‐deficient (MFAP4 −/− ) and wild‐type mice were subjected to aortic banding surgery and isoproterenol to establish models of cardiac remodeling. We also evaluated the functional effects of MFAP4 on cardiac hypertrophy, fibrosis, and cardiac electrical remodeling. The expression of MFAP4 was increased in the animal cardiac remodeling models induced by pressure overload and isoproterenol. After challenge of 8 weeks of aortic banding or 2 weeks of intraperitoneal isoproterenol, MFAP4 −/− mice exhibited lower levels of cardiac fibrosis and fewer ventricular arrhythmias than wild‐type mice. However, there was no significant effect on cardiomyocyte hypertrophy. In addition, there was no significant difference in cardiac fibrosis severity, hypertrophy, or ventricular arrhythmia incidence between wild‐type‐sham and knockout‐sham mice. Conclusions These findings are the first to demonstrate that MFAP4 deficiency inhibits cardiac fibrosis and ventricular arrhythmias after challenge with 8 weeks of aortic banding or 2 weeks of intraperitoneal isoproterenol but does not significantly affect the hypertrophy response. In addition, MFAP4 deficiency had no significant effect on cardiac fibrosis, hypertrophy, or ventricular arrhythmia in the sham group in this study.

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

Circulation ◽

10.1161/circ.132.suppl_3.14664 ◽

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.

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

Cardiology ◽

10.1159/000505318 ◽

2020 ◽

Vol 145 (3) ◽

pp. 187-198 ◽

Cited By ~ 1

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.

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Abstract P140: Mutant Mice Carrying Global Loss Of Npr1 Exhibit Cardiac Fibrosis, Hypertrophy, And Congestive Heart Failure: Implication Of TGF-Beta/SMAD Signaling Pathway

Hypertension ◽

10.1161/hyp.78.suppl_1.p140 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Chandramohan Ramasamy ◽

Umadevi Subramanian ◽

Kailash N Pandey

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Growth Factor ◽

Cardiac Hypertrophy ◽

Signaling Pathway ◽

Cardiac Fibrosis ◽

Left Ventricular ◽

Mutant Mice ◽

Null Mutant ◽

Wild Type

The cardiac hormones, atrial and brain natriuretic peptides (ANP and BNP) bind to natriuretic peptide receptor-A (NPRA), which synthesizes the second messenger cGMP. The objective of this study was to determine the underlying mechanisms that regulate the development of cardiac hypertrophy, fibrosis, and congestive heart failure (CHF) in Npr1 (encoding NPRA) gene-knockout mice. The Npr1 null mutant ( Npr1 -/- , 0-copy), heterozygous ( Npr1 +/- , 1-copy), and wild-type ( Npr1 +/+ , 2-copy) mice were orally administered with transforming growth factor-β1 receptor I (TGF-β1R1) antagonist, GW788388 (2 mg/kg/day) by oral gavage for 28 days. The left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVEDS), posterior wall thickness (PWT), and percent fractional shortening (FS) were analyzed by echocardiography. The heart was isolated and used for the analysis of fibrotic markers using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot methods. The heart weight-to-body weight (HW/BW) ratio, LVEDD, LVEDS and PWT were significantly (p<0.005) increased in Npr1 -/- and Npr1 +/- mice than wild-type Npr1 +/+ mice. The FS was greatly reduced in Npr1 -/- and Npr1 +/- mice compared with Npr1 +/+ mice. The Npr1 -/- null mutant (0-copy) mice showed 52% increase in HW/BW ratio and 6-fold induction of cardiac fibrosis as compared with 2-copy control mice. The cardiac expression of fibrotic markers including collagen-1a (COL-1a; 3.5-fold), connective tissue growth factor (CTGF; 5-fold), α-smooth muscle actin (α-SMA; 4-fold), TGF-β1RI (4-fold), TGF-β1RII (3.5-fold), and SMAD-2/3 proteins (3-to-5 fold) were significantly increased in Npr1 -/- and Npr1 +/- mutant mice compared with age-matched Npr1 +/+ animals. The treatment with TGF-β1R1 antagonist, significantly (p<0.001) prevented the cardiac hypertrophy, fibrosis, CHF, and down-regulated the expression of fibrotic markers and SMAD proteins in mutant mice. The LVEDD, LVEDS, and FS were significantly (p<0.001) improved in the drug treated Npr1 -/- mice. The present results indicate that the cardiac hypertrophy, fibrosis, and CHF in Npr1 mutant mice is regulated through the TGF-β1-mediated SMAD-dependent signaling pathway.

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Abstract 2021: Adrenergic Receptor Polymorphisms and Prevention of Ventricular Arrhythmias with Bucindolol in Patients with Heart Failure

Circulation ◽

10.1161/circ.116.suppl_16.ii_437-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

William Sauer ◽

Christopher M Lowery ◽

Chakra Budhathoki ◽

Brian D Lowes ◽

Michael R Bristow

Keyword(s):

Heart Failure ◽

Adrenergic Receptor ◽

Ventricular Arrhythmias ◽

Nyha Class ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Loss Of Function ◽

Wild Type ◽

Ventricular Ejection Fraction ◽

Β Blocker

Background: β-blockers have been shown to prevent ventricular arrhythmias (VT/VF) in patients with low left ventricular ejection fraction (LVEF) and chronic heart failure (CHF). We hypothesized that there may be genotype specific responses to β-blocker therapy for prevention of VT/VF. Methods: The β-blocker Evaluation of Survival Trial (BEST) is a randomized trial of bucindolol in patients with NYHA Class III – IV CHF and LVEF ≤0.35. From a substudy of 1040 genotyped subjects, we identified those with the high functioning Arg389 β1 adrenergic receptor polymorphism and the loss of function 322–325 α2c adrenergic receptor deletion polymorphism. The incidence of VT/VF was prospectively recorded as an adverse event during the trial. Results: Of the 1040 subjects in the genotyped cohort, there were a total of 493 Arg389 β1 homozygotes vs. 547 Gly389 carriers and 207 α2c deletion carriers vs. 833 wild-types. The diplotypes included 418 subjects with both Arg/Arg389 β1 receptors and wild type α2c, 484 with one of these, and 134 carrying both the α2c deletion and β1 Gly389. For the genetic substudy, bucindolol was associated with less VT/VF that placebo (5.5% vs. 12.1%; p<0.01) There was a significant drug-gene interaction for prevention of VT/VF with both polymorphisms (β1 overall p<0.01; α2c overall p<0.01). Arg389 homozygotes randomized to bucindolol had a lower incidence of VT/VF during the trial than those randomized to placebo (4.3% vs. 14.4%; P<0.01) as for wild type α2c homozygotes (5.4% vs. 12.7%; p<0.01). This reduction in VT/VF was not significant in other genotypes (β1 Gly389 carriers: 6.6% vs. 10.4%; P=0.13 and α2c deletion carriers: 4.9% vs. 10.6%; P=0.19). Subjects with the Arg/Arg389 β1/wild type α2c receptor diplotype randomized to bucindolol had a lower rate of VT/VF occurrence than those with only one or neither of these genotypes (both: 4.7% vs. 14.6%; p<0.01; one: 4.9% vs. 11.2%; p=0.01; neither: 8.5% vs. 9.3%; p=1.0). Conclusion: Subjects with CHF and Arg/Arg389 β1 or wildtype α2c adrenergic receptors treated with bucindolol had a lower rate of VT/VF than those randomized to placebo. This treatment effect was not observed in the population of β1 Gly389 or the α2c deletion carriers, indicating a pharmacogenetic interaction.

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P2254Impaired autophagic off-rate causes cardiac aging in progeria mouse model

European Heart Journal ◽

10.1093/eurheartj/ehz748.0732 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

T Kamihara ◽

Y Kureishi Bando ◽

K Nishimura ◽

R Yasheng ◽

R Ozaki ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Dna Damage ◽

Mouse Model ◽

Cardiac Remodeling ◽

Dna Helicase ◽

Left Ventricular ◽

Myocardial Remodeling ◽

Wild Type ◽

Cardiac Aging

Abstract Background/Introduction Aging is known to be one of the primary causes of heart failure. Werner syndrome is one of the aging disorder that caused by dysfunction of DNA helicase-regulatory protein (WRN). However, there is little information whether WRN may cause any specific myocardial remodeling and vulnability for heart failure. More interestingly, ample evidences demonstrated DNA damage occurred in progeria causes autophagic disorder, contributing to aging phenotype, in short, autophagy may be a guardian of the genome. Although autophagic disorder has been implicated to cause cardiac remodeling in heart failure; however, it remains uncertain whether autophagic disorder may link to the mechanism of aging-induced cardiac remodeling. Purpose To elucidate whether autophagic disorder may be mechanistically responsible for cardiac aging we hypothesized whether aging-related DNA injury may affect autophagy that may lead to myocardial remodeling. Methods We employed progeria mouse model harboring amino acid (AA) substitution of WRN at position 577 (WRN-K577M), which were evaluated in terms of cardiac function and remodeling at the phase of adult (18 week-old). Results WRN-K577M exhibited diffuse left-ventricular (LV) hypertrophy, enhanced fibrosis, and diastolic LV dysfunction with preserved systolic ejection fraction. DNA microarray analysis of WRN-K577M heart revealed that the 253 genes were upregulated compared to age- and gender-matched wild-type counterpart. Sixteen genes were increased >4 fold higher than wild-type as follows: hypertrophy (Myh7, Klkb11), fibrosis (Fgf21, CTGF), inflammatory molecules (Ap1s3, Pla2g2e, Has1, MMP9), and oxidative stress (catalase). Cardiac aging markers (PARP-1, p53 and γH2AX) increased in heart of WRN-K577M with concomitant increase in oxidative stress (DHE staining) and apoptosis (TUNEL). Notably, autophagic turnover markers (i.e., increased on-rate of autophagy; p62 and LC3-II/I) were increased in myocardium of WRN-K577M, which was refractory to fasting-induced autophagic activation, indicating the on-rate step of autophagy is pathologically augmented under cardiac aging observed in WRN-K577M. In contrast, one of the key regulators of autophagy is the target of rapamycin, TOR kinase, which is the major inhibitory signal that shuts off autophagy with concomitant activation of Akt signaling. In contrast, blockade of the lysosomal fusion into autophagosome by systemic treatment with chloroquine (50 microg/g body weight) reduced LC3-II/I ratio, indicating the retarded off-rate of autophagy mediated by impaired lysosome fusion is presumably responsible for cardiac aging. Conclusion(s) DNA damage impairs autophagy in heart, leading to myocardial oxidative stress. In WRN-mutant progeria model, off-rate disorder of cardiac autophagy is, at least in part, the cause of increase in oxidative stress and inflammation in heart leading to HFpEF.

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Abstract 99: IL10-inhibits Fibroblast Progenitor Cell-mediated Cardiac Fibrosis in Pressure-overloaded Myocardium

Circulation Research ◽

10.1161/res.119.suppl_1.99 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Suresh K Verma ◽

Venkata N Garikipati ◽

Prasanna Krishnamurthy ◽

Cindy Benedict ◽

Emily Nickoloff ◽

...

Keyword(s):

Heart Failure ◽

Bone Marrow ◽

Cardiac Fibrosis ◽

Critical Role ◽

Pressure Overload ◽

Interleukin 10 ◽

Left Ventricular ◽

Lv Function ◽

Wild Type ◽

Mirna Array

Background: Activated fibroblasts (myoFBs) play critical role in cardiac fibrosis, however, their origin in diseased heart remains uncertain. Recent studies suggest the contribution of bone marrow fibroblasts progenitor cells (BM-FPC) in pressure overload (PO)-induced cardiac fibrosis. Previously we have shown that interleukin-10 suppress PO-induced cardiac fibrosis, however, its role on inhibition of BM-FPC-mediated fibrosis is not known. Thus, we hypothesized that IL-10 inhibits PO-induced homing and transition of BM-FPC to myoFBs and therefore, attenuates cardiac fibrosis. Methods and Results: Cardiac fibrosis was induced in Wild-type (WT) and IL-10-knockout (KO) mice by transverse aortic constriction (TAC). TAC-induced left ventricular (LV) dysfunction and fibrosis were further exaggerated in KO mice. Systemic recombinant IL-10 administration markedly improved LV function and inhibited PO-induced cardiac fibrosis. PO-enhanced FPC (Prominin1 + cells) mobilization and homing in IL-10 KO mice compared to WT mice. Furthermore, bone marrow transplantation (BMT) experiment was performed wherein WT marrow from GFP mice was repopulated in IL-10 KO mice. FPC mobilization was significantly reduced in BMT-IL10 KO mice compared to IL-10 KO mice after TAC. Furthermore, immunofluorescence result in BMT mice showed that subsets of myoFBs are derived from BM after TAC. To identify the molecular mechanism, wild type BM-FPC were treated with TGFβ 2 with or without IL10. IL10 treatment significantly inhibits TGFβ 2 -induced FPC to myoFBs transition. As miRNAs are key players in cardiac fibrosis, next we performed fibrosis-associated miRNA profiling using miRNA array kit. TGFβ 2 -induced miR-208, 155, 21 and 145 expression was markedly inhibited by IL-10. Conclusion: Taken together, our findings suggest that both reduced homing to heart and transition of FPC to myofibroblasts mediate anti-fibrotic effect of IL10 during PO-induced heart failure. Ongoing investigations using molecular approaches will provide a better understanding on the mechanistic and therapeutic aspects of IL10 on PO-induced cardiac fibrosis and heart failure.

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Abstract 64: Conditional Knockout of Activin Like Kinase-1 (ALK-1) Leads to Heart Failure Without Maladaptive Remodeling

Circulation Research ◽

10.1161/res.117.suppl_1.64 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Kevin Morine ◽

Vikram Paruchuri ◽

Xiaoying Qiao ◽

Emily Mackey ◽

Jonathan Levine ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Remodeling ◽

Cardiac Fibrosis ◽

Type I Collagen ◽

Diastolic Pressure ◽

Systolic Pressure ◽

Left Ventricular ◽

Conditional Knockout ◽

Type I ◽

Total Body Mass

Activin like kinase 1 (ALK1) mediates signaling via the TGFb family of ligands. ALK1 activity promotes endothelial proliferation and migration. Reduced ALK1 activity is associated with arteriovenous malformations. No studies have examined the effect of global ALK1 deletion on indices of cardiac remodeling. We hypothesized that reduced levels of ALK1 promote maladaptive cardiac remodeling. Methods: We employed an ALK1 conditional knockout mice (cKO) harboring the ROSA26-CreER knock-in allele whereby a single dose of intraperitoneal tamoxifen triggered ubiquitous Cre recombinase mediated excision of floxed ALK1 alleles. Tamoxifen treated wild-type (WT-Tam; n=5) and vehicle treated ALK1-cKO mice (cKO-Veh; n=5) served as controls for tamoxifen treated ALK1-cKO mice (cKO-Tam; n=15). Results: ALK1 cKO-Tam mice demonstrated reduced 14-day survival compared to cKO-Veh controls (33% vs 100%, respectively, p<0.01). Seven days after treatment, ALK1 cKO mice began to exhibit reduced left ventricular (LV) fractional shortening, progressive LV dilation, and gastrointestinal bleeding. After 14 days total body mass was reduced, but LV and lung mass increased in cKO-Tam not cKO-Veh mice. Peak LV systolic pressure, contractility, and arterial elastance were reduced, but LV end-diastolic pressure and stroke volume increased in cKO-Tam, not cKO-Veh mice. LV ALK1 mRNA and protein levels were reduced in cKO-Tam, not cKO-Veh mice. LV levels of other TGFb-family ligands and receptors (ALK5, TBRII, BMPRII, Endoglin, BMP7, BMP9, and TGFB1) were unchanged between groups. Cardiomyocyte area and LV levels of BNP were increased in cKO-Tam mice, but LV levels of b-MHC, SerCA, and calcineurin were unchanged. No increase in cardiac fibrosis Type I collagen, CTGF, or PAI-1 levels were observed between groups. No differences were observed for any variable studied between cKO-Veh and WT-Tam mice. Conclusion: Global deletion of ALK1 is associated with the development of high output heart failure without maladaptive remodeling. Future studies exploring the functional role of ALK1 in cardiac remodeling are required.

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Left ventricular noncompaction—a rare cause of triad: heart failure, ventricular arrhythmias, and systemic embolic events: a case report

Journal of Medical Case Reports ◽

10.1186/s13256-021-02862-x ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Despina Toader ◽

Alina Paraschiv ◽

Petrișor Tudorașcu ◽

Diana Tudorașcu ◽

Constantin Bataiosu ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Magnetic Resonance ◽

Magnetic Resonance ◽

Left Ventricle ◽

Ventricular Arrhythmias ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Left Ventricular Noncompaction ◽

Ventricular Noncompaction ◽

The Right

Abstract Background Left ventricular noncompaction is a rare cardiomyopathy characterized by a thin, compacted epicardial layer and a noncompacted endocardial layer, with trabeculations and recesses that communicate with the left ventricular cavity. In the advanced stage of the disease, the classical triad of heart failure, ventricular arrhythmia, and systemic embolization is common. Segments involved are the apex and mid inferior and lateral walls. The right ventricular apex may be affected as well. Case presentation A 29-year-old Caucasian male was hospitalized with dyspnea and fatigue at minimal exertion during the last months before admission. He also described a history of edema of the legs and abdominal pain in the last weeks. Physical examination revealed dyspnea, pulmonary rales, cardiomegaly, hepatomegaly, and splenomegaly. Electrocardiography showed sinus rhythm with nonspecific repolarization changes. Twenty-four-hour Holter monitoring identified ventricular tachycardia episodes with right bundle branch block morphology. Transthoracic echocardiography at admission revealed dilated left ventricle with trabeculations located predominantly at the apex but also in the apical and mid portion of lateral and inferior wall; end-systolic ratio of noncompacted to compacted layers > 2; moderate mitral regurgitation; and reduced left ventricular ejection fraction. Between apical trabeculations, multiple thrombi were found. The right ventricle had normal morphology and function. Speckle-tracking echocardiography also revealed systolic left ventricle dysfunction and solid body rotation. Abdominal echocardiography showed hepatomegaly and splenomegaly. Abdominal computed tomography was suggestive for hepatic and renal infarctions. Laboratory tests revealed high levels of N-terminal pro-brain natriuretic peptide and liver enzymes. Cardiac magnetic resonance evaluation at 1 month after discharge confirmed the diagnosis. The patient received anticoagulants, antiarrhythmics, and heart failure treatment. After 2 months, before device implantation, he presented clinical improvement, and echocardiographic evaluation did not detect thrombi in the left ventricle. Coronary angiography was within normal range. A cardioverter defibrillator was implanted for prevention of sudden cardiac death. Conclusions Left ventricular noncompaction is rare cardiomyopathy, but it should always be considered as a possible diagnosis in a patient hospitalized with heart failure, ventricular arrhythmias, and systemic embolic events. Echocardiography and cardiac magnetic resonance are essential imaging tools for diagnosis and follow-up.

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Abstract 17311: Ventricular Arrhythmias and Fibrosis in Patients With Heart Failure and Preserved Ejection Fraction

Circulation ◽

10.1161/circ.142.suppl_3.17311 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Natasha Cuk ◽

Jae H Cho ◽

Donghee Han ◽

Joseph E Ebinger ◽

Eugenio Cingolani

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Cardiac Mri ◽

Ventricular Arrhythmias ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Preserved Ejection Fraction ◽

Ventricular Ejection Fraction ◽

Patients With Heart Failure ◽

Ventricular Fibrosis

Introduction: Sudden death due to ventricular arrhythmias (VA) is one of the main causes of mortality in patients with heart failure and preserved ejection fraction (HFpEF). Ventricular fibrosis in HFpEF has been suspected as a substrate of VA, but the degree of fibrosis has not been well characterized. Hypothesis: HFpEF patients with increased degree of fibrosis will manifest more VA. Methods: Cedars-Sinai medical records were probed using Deep 6 artificial intelligence data extraction software to identify patients with HFpEF who underwent cardiac magnetic resonance imaging (MRI). MRI of identified patients were reviewed to measure extra-cellular volume (ECV) and degree of fibrosis. Ambulatory ECG monitoring (Ziopatch) of those patients were also reviewed to study the prevalence of arrhythmias. Results: A total of 12 HFpEF patients who underwent cardiac MRI were identified. Patients were elderly (mean age 70.3 ± 7.1), predominantly female (83%), and overweight (mean BMI 32 ± 9). Comorbidities included hypertension (83%), dyslipidemia (75%), and coronary artery disease (67%). Mean left ventricular ejection fraction by echocardiogram was 63 ± 8.7%. QTc as measured on ECG was not significantly prolonged (432 ± 15 ms). ECV was normal in those patients for whom it was available (24.2 ± 3.1, n = 9) with 3/12 patients (25%) demonstrating ventricular fibrosis by MRI (average burden of 9.6 ± 5.9%). Ziopatch was obtained in 8/12 patients (including all 3 patients with fibrosis) and non-sustained ventricular tachycardia (NSVT) was identified in 5/8 (62.5%). One patient with NSVT and without fibrosis on MRI also had a sustained VA recorded. In those patients who had Ziopatch monitoring, there was no association between presence of fibrosis and NSVT (X2 = 0.035, p = 0.85). Conclusions: Ventricular fibrosis was present in 25% of HFpEF patients in this study and NSVT was observed in 62.5% of those patients with HFpEF who had Ziopatch monitoring. The presence of fibrosis by Cardiac MRI was not associated with NSVT in this study; however, the size of the cohort precludes broadly generalizable conclusions about this association. Further investigation is required to better understand the relationship between ventricular fibrosis by MRI and VA in patients with HFpEF.

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