Amar J. Azad

A titin truncating variant linked to atrial fibrillation increases atrial profibrotic signalling and cholinergic sensitivity

Max J. Cumberland, Albert Dasí, Naeramit Sontayananon, Alan Marcus et autres

AIMS: Titin truncating variants (TTNtv) are a major genetic cause of dilated cardiomyopathy (DCM), accounting for approximately 25% of familial cases. Atrial fibrillation (AF) frequently occurs in DCM patients carrying TTNtv and may precede overt ventricular dysfunction, suggesting an atrial-specific disease mechanism. …

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Lipid@polymer hybrid nanoparticles for efficient siRNA transport across the lung barriers: Mechanistic insights into the role of Ionizable lipids

Susy Brusco, Ersilia Villano, Teresa Silvestri, Amar J. Azad et autres

Building on growing evidence that ionizable lipids improve RNA delivery, in this work, we developed ionizable lipid/poly(lactic-co-glycolic acid) hybrid nanoparticles (iLipid@PLGA hNPs), consisting in a PLGA core modified at surface with either 1,2-dioleoyloxy-3-dimethylaminopropane (DODMA), 1,2-dioleoyl-3-trimethylammonium-propane (DODAP), or the branched-tail proprietary amino lipid …

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Transient HA-100 exposure improves aggregate uniformity and cell-cell contact stability in suspension human pluripotent stem cell cultures

Preeti Khurana, Amar J. Azad, Nikola Kolundžić, Mirjana Liović et autres

BACKGROUND AIMS: Human pluripotent stem cell (hPSC) manufacturing workflows frequently rely on suspension aggregation, yet inter-line and batch-to-batch variability in aggregate formation can compromise process consistency and downstream differentiation performance. We evaluated whether a short exposure to HA-100, a small-molecule inhibitor of …

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Early atrial remodeling: A driver of arrhythmia in Fabry disease

Ashwin Roy, Christopher O’Shea, Albert Dasí, Leena K. Patel et autres

Mechanosensitive biochemical imprinting of the talin interaction with DLC1 regulates RhoA activity and cardiomyocyte remodeling

Emilie Marhuenda, Ioannis Xanthis, Poppy O. Smith, Aishwarya Prakash et autres

During heart disease, the cardiac extracellular matrix (ECM) undergoes a structural and mechanical transformation. Cardiomyocytes sense the mechanical properties of their environment, leading to phenotypic remodeling. A critical component of the ECM mechanosensing machinery, including the protein talin, is organized at the …

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BS42 Mechanical imprinting of the talin interaction with DLC1 regulates RHOA activity and cardiomyocyte remodelling

Emilie Marhuenda, Ioannis Xanthis, Aishwarya Prakash, Till Kallem et autres

Introduction During heart disease, the cardiac extracellular matrix (ECM) mechanically transforms, resulting in the stiffening of the ECM. Cardiomyocytes sense this ECM change, leading to phenotypic remodelling. A key part of the cardiomyocyte mechanosensing machinery is organised at the costamere; integrins and …

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Unveiling tissue-specific transcriptional adaptations in iPSC-derived fibroblasts via co-culture systems

Amar J. Azad, Alessandro Bentivogli, Henrike Germar, Dana Wörz et autres

BACKGROUND: Induced pluripotent stem cell-derived fibroblasts (iFBs) hold promise for autologous disease modelling, but their ability to replicate tissue-specific fibroblast characteristics remains unclear. Fibroblasts exhibit significant heterogeneity, with distinct subtypes playing critical roles in organ function and integrity. This study investigates whether …

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Substrate stiffness-dependent metabolic reprogramming of iPSC-derived cardiomyocytes on physiological PDMS polymers

Leena Patel, Bryan P. Marzullo, Jonathan Barlow, Himani Rana et autres

Many cardiac pathologies are characterised by increased stiffness of the myocardium, due to excess deposition of extracellular matrix (ECM) proteins and structural remodelling, impacting the behaviour of cardiomyocytes (CMs). Metabolism of CMs shifts in cardiac pathologies, with the healthy heart primarily utilising …

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Early Atrial Remodeling Drives Arrhythmia in Fabry Disease

Ashwin Roy, Christopher O’Shea, Albert Dasí, Leena K. Patel et autres

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by α-Gal A (α-galactosidase A) deficiency, resulting in multiorgan accumulation of sphingolipid, namely globotriaosylceramide. This triggers ventricular myocardial hypertrophy, fibrosis, and inflammation, driving arrhythmia and sudden death. Atrial fibrillation is common, …

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Filamin C dimerisation is regulated by HSPB7

Zihao Wang, Guodong Cao, Miranda P. Collier, Xingyu Qiu et autres

The biomechanical properties and responses of tissues underpin a variety important of physiological functions and pathologies. In striated muscle, the actin-binding protein filamin C (FLNC) is a key protein whose variants causative for a wide range of cardiomyopathies and musculoskeletal pathologies. FLNC …

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A titin truncating variant linked to atrial fibrillation increases atrial profibrotic signalling and cholinergic sensitivity.

Max J. Cumberland, Albert Dasí, Naeramit Sontayananon, Alan Marcus et autres

Acknowledgements: We thank Dirk-Peter Herten and Ashwin Roy for their helpful discussions and support in the preparation of this manuscript.

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Characterisation of infantile cardiomyopathy in Alström syndrome using ALMS1 knockout induced pluripotent stem cell derived cardiomyocyte model

Leena Patel, Ashwin Roy, Jonathan Barlow, Christopher O’Shea et autres

Alström syndrome (AS) is an inherited rare ciliopathy characterised by multi-organ dysfunction and premature cardiovascular disease. This may manifest as an infantile-onset dilated cardiomyopathy with significant associated mortality. An adult-onset restrictive cardiomyopathy may also feature later in life. Loss of function pathogenic …

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