Intramyocardial Adiposity After Myocardial Infarction

Pouliopoulos, Jim; Chik, W.; Kanthan, A.; Sivagangabalan, Gopal; Barry, Michael A.; Fahmy, Peter; Midekin, Christine; Lu, Juntang; Kizana, Eddy; Thomas, Stuart P.; Thiagalingam, Aravinda; Kovoor, Pramesh

doi:10.1161/circulationaha.113.002238

Cited by 99 publications

(35 citation statements)

References 50 publications

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“…The abundantly present ECM is interlaced with phenotypically diverse groups of cells: interstitial fibroblast-like cells (both functionally and structurally heterogeneous, endothelial cells, vascular smooth muscle, surviving cardiomyocytes, immune cells, neurons, and adipocytes [18, 19] (Fig. 1B,C).…”

Section: The Scar – a Living Tissuementioning

confidence: 99%

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The Living Scar – Cardiac Fibroblasts and the Injured Heart

Rog-Zielinska

Norris

Kohl

et al. 2016

Trends in Molecular Medicine

142

102

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Cardiac scars, often perceived as “dead” tissue, are very much alive, with heterocellular activity ensuring the maintenance of structural and mechanical integrity following heart injury. To form a scar, non-myocytes such as fibroblasts, proliferate and are recruited from intra- and extra-cardiac sources. Fibroblasts perform important autocrine and paracrine signalling functions. They also establish mechanical and, as is increasingly evident, electrical junctions with other cells. While fibroblasts were previously thought to act simply as electrical insulators, they may be electrically connected among themselves and, under certain circumstances, to other cells, including cardiomyocytes. A better understanding of these interactions will help target scar structure and function and facilitate the development of novel therapies aimed at modifying scar properties for patient benefit. This review explores available insight and recent concepts on fibroblast integration in the heart, and highlights potential avenues for harnessing their roles to optimise scar function following heart injury such as infarction, and therapeutic interventions such as ablation.

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Section: The Scar – a Living Tissuementioning

confidence: 99%

“…immune cells) are more than likely. Interactions of fibroblasts with adipocytes within the scar has been suggested to affect conduction velocity via electrotonic source-sink alterations in human MI studies [19], although no mechanism of electrotonic coupling between these cell types has been identified so far [18]. …”

Section: The Many Roles Of Scar Fibroblastsmentioning

confidence: 99%

The Living Scar – Cardiac Fibroblasts and the Injured Heart

Rog-Zielinska

Norris

Kohl

et al. 2016

Trends in Molecular Medicine

142

102

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“…On heart injuries, such as myocardial infarction, millions of cardiomyocytes undergo irreversible necrosis and infarct areas are replaced with fibroblasts and further differentiate into nonfunctional tissues like fibrotic scar [2] or adipose tissue [3, 4]. Recently, targeting fibroblasts by introduction of three transcription factors Gata4, Mef2C and Tbx5 (G, M and T), and reprogramming them into cardiomyocyte-like cells have shown therapeutic potential [5–8].…”

Section: Introductionmentioning

confidence: 99%

Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts

et al. 2016

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Generation of induced cardiomyocytes (iCMs) directly from fibroblasts offers a great opportunity for cardiac disease modeling and cardiac regeneration. A major challenge of iCM generation is the low conversion rate. To address this issue, we attempted to identify small molecules that could potentiate the reprogramming ability towards cardiac fate by removing inhibitory roadblocks. Using mouse embryonic fibroblasts as the starting cell source, we first screened 47 cardiac development related epigenetic and transcription factors, and identified an unexpected role of H3K4 methyltransferase Mll1 and related factor Men1 in inhibiting iCM reprogramming. We then applied small molecules (MM408 and MI503) of Mll1 pathway inhibitors and observed an improved efficiency in converting embryonic fibroblasts and cardiac fibroblasts into functional cardiomyocyte-like cells. We further observed that these inhibitors directly suppressed the expression of Mll1 target gene Ebf1 involved in adipocyte differentiation. Consequently, Mll1 inhibition significantly decreased the formation of adipocytes during iCM induction. Therefore, Mll1 inhibitors likely increased iCM efficiency by suppressing alternative lineage gene expression. Our studies show that targeting Mll1 dependent H3K4 methyltransferase activity provides specificity in the process of cardiac reprogramming. These findings shed new light on the molecular mechanisms underlying cardiac conversion of fibroblasts and provide novel targets and small molecules to improve iCM reprogramming for clinical applications.

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“…In a recent study, Pouliopoulos et al have demonstrated that increased intramyocardial adipose tissue in sheep is significantly associated with altered electrophysiological properties such as slower conduction velocity and lower electrogram amplitude, and has an impact on scar-related VT circuits. 10 Computed tomography (CT) offers higher spatial resolution and can identify fat tissue based on CT attenuation density values (Hounsfield units, HU). 3–6 In addition, contrast-enhanced computed tomography (CE-CT) can accurately define anatomical structures including chamber boundaries and coronary arteries, which can be integrated into electroanatomic mapping (EAM) systems.…”

Section: Introductionmentioning

confidence: 99%

New insight into scar-related ventricular tachycardia circuits in ischemic cardiomyopathy: Fat deposition after myocardial infarction on computed tomography--A pilot study

Sasaki¹,

Calkins²,

Miller³

et al. 2015

Heart Rhythm

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Background Myocardial fat deposition (FAT-DEP) has been frequently observed in regions of chronic myocardial infarction in patients with ischemic cardiomyopathy (ICM). The role of FAT-DEP within scar-related ventricular tachycardia (VT) circuits has not been investigated. Objective This pilot study aimed to assess the impact of myocardial FAT-DEP on local electrograms and VT circuits in patients with ICM. Methods Contrast-enhanced computed tomography (CE-CT) was performed in 22 patients with ischemic VT. Electroanatomic map (EAM) points were registered to corresponding CE-CT images. Myocardial FAT-DEP were identified and characterized using a post-processing image overlay that highlighted areas below 0 Hounsfield units (HU). The mean attenuation of local myocardial regions corresponding to sampled electrograms was measured on short axis images. The associations of mean attenuation with bipolar and unipolar amplitudes, left ventricular (LV) wall thickness and VT circuit sites were investigated. Results Of 1801 EAM points, 519 (28.8%) were located in regions with FAT-DEP. Significant differences were observed in mean intensity (23.2±35.6 vs. 81.7±21.9 HU, P<0.001), bipolar (0.75±0.83 vs 2.9±2.4 mV, P<0.001) and unipolar (3.1±1.7 vs. 7.4±4.3 mV, P<0.001) amplitudes and LV wall thickness (5.2±1.7 vs. 8.2±2.5 mm, P<0.001) between regions with and without FAT-DEP. Lower HU was strongly associated with lower bipolar and unipolar amplitude (P<0.0001, respectively). Importantly, FAT-DEP was associated with critical VT circuit sites with fractionated or isolated potentials. Conclusions FAT-DEP was associated with electrogram features and VT circuit sites. Further work will be needed to determine whether FAT-DEP plays a causal role in the generation of ischemic scar-related VT circuits.

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Intramyocardial Adiposity After Myocardial Infarction

Abstract: Intramyocardial adiposity, in association with myocardial discontinuity within left ventricular scar borders, is a significant factor associated with altered electrophysiological properties, aberrant connexin43 expression, and increased propensity for VT after MI.

Cited by 99 publications

References 50 publications

The Living Scar – Cardiac Fibroblasts and the Injured Heart

The Living Scar – Cardiac Fibroblasts and the Injured Heart

Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts

New insight into scar-related ventricular tachycardia circuits in ischemic cardiomyopathy: Fat deposition after myocardial infarction on computed tomography--A pilot study

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