What is the clinical evidence from this study?

Population: Dilated cardiomyopathy (n=4). Intervention: Dilated cardiomyopathy (DCM) patient-derived hiPSC-CMs vs. Healthy control-derived hiPSC-CMs. Primary outcome: Cellular signalling (PKA and ERK activity) and functional properties (calcium handling, contractility, electrophysiology).

What does this research mean for the field?

A human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) pipeline can successfully identify patient-specific molecular signaling and functional alterations in dilated cardiomyopathy. Novelty: ClaimNovelty.METHODOLOGICAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

Characterize and compare patient-specific G protein-coupled receptor signalling and functional properties in human induced pluripotent stem cell-derived cardiomyocytes from patients with dilated cardiomyopathy versus healthy controls.

September 14, 2026npj Biomedical Innovations.Open Access

Evaluating and comparing the signalling and functional landscape of hiPSC-CMs derived from patients with dilated cardiomyopathy

View Full Paper

Ask AI

Bookmark

Key result

DCM hiPSC-CMs exhibit distinct, patient-specific signaling and functional responses to GPCR-targeting ligands.

Why the study?

Incomplete molecular knowledge of dilated cardiomyopathy pathophysiology poses challenges for discovering new therapeutic agents and understanding variable patient outcomes.

Comparison

hiPSC-CMs from DCM patients treated with GPCR-targeting ligands vs hiPSC-CMs from healthy controls

Design

Preclinical study using hiPSC-CMs with single cell resolution biosensor assays

Authors

GCGiada CastagnolaMcGill University DLDiego LoggiaMcGill University KBKyla BourqueMcGill University

Discussion

Member takes

Implication

May support molecular subtyping to tailor DCM therapy; leaves open whether this improves outcomes in prospective validation.

Key Points

Characterize and compare patient-specific G protein-coupled receptor signalling and functional properties in human induced pluripotent stem cell-derived cardiomyocytes from patients with dilated cardiomyopathy versus healthy controls.
Reprogrammed peripheral blood mononuclear cells from two patients with idiopathic dilated cardiomyopathy and two age- and sex-matched healthy controls into hiPSC lines, validating pluripotency, trilineage differentiation, and normal karyotypes.
Differentiated hiPSC lines into cardiomyocytes (~85% purity) exhibiting spontaneous beating and expression of cardiac markers MYH7, TNNT2, and TNNI3.
Transduced cardiomyocytes with AAV6/9 expressing genetically encoded biosensors (ExRai-AKAR and EKAR) to quantify nuclear and cytosolic PKA and ERK activity via FRET following stimulation with GPCR-targeted ligands.
Responses to forskolin demonstrated reduced overall PKA system capacity across nuclear and cytosolic compartments in male Patient 2 relative to male Control 2, whereas female Patient 1 showed capacity comparable to female Control 1.
Stimulation with isoproterenol and epinephrine elicited significantly higher nuclear PKA activation in Patient 1 compared to Patient 2, indicating patient-specific upregulation of beta-adrenergic receptor signalling.
No cytosolic or nuclear PKA activation was observed across any subjects in response to canonical or biased angiotensin II type 1 receptor ligands.

Structured PICO

Population

4 adults (mean age 47 years, 50% female), including 2 with dilated cardiomyopathy and 2 healthy controls, whose blood samples were used to generate hiPSC-derived cardiomyocytes.

Exposure

In vitro treatment with disease-relevant G protein-coupled receptor (GPCR)-targeting ligands (including angiotensin II, isoproterenol, norepinephrine, epinephrine, phenylephrine, carvedilol, and endothelin-1).

Comparator

Vehicle control and hiPSC-CMs from healthy control subjects.

Outcome

Cellular signaling (nuclear and cytosolic PKA and ERK activity measured via biosensors) and functional properties (calcium handling, contractility, and electrophysiology).surrogate

This study establishes a patient-specific hiPSC-CM pipeline that reveals individualized molecular and functional phenotypes in dilated cardiomyopathy, highlighting the potential for personalized medicine.

Limitations

Small sample size (only 4 subjects) not powered to draw disease-level conclusions
Relatively immature state of hiPSC-CMs compared to adult cardiomyocytes
In vitro model may not fully replicate in vivo physiology
Difficulty in matching single-cell responses with markers of cell identity and maturation

Cite This Study

Castagnola et al. (2026) studied Dilated cardiomyopathy (n=4). Dilated cardiomyopathy (DCM) patient-derived hiPSC-CMs vs. Healthy control-derived hiPSC-CMs was evaluated on Cellular signalling (PKA and ERK activity) and functional properties (calcium handling, contractility, electrophysiology). Human induced pluripotent stem cell-derived cardiomyocytes from patients with dilated cardiomyopathy exhibited distinct, patient-specific molecular signalling and functional profiles in response to GPCR-targeting ligands.

synapsesocial.com/papers/6aa7afef79e9260bc85aacb6 https://doi.org/10.1038/s44385-026-00111-8

Topics

Heart failure HFrEF treatment

View Full Paper

Ask AI

Bookmark

Evaluating and comparing the signalling and functional landscape of hiPSC-CMs derived from patients with dilated cardiomyopathy

Discussion

Member takes

Implication

Key Points

Structured PICO

Limitations

Cite This Study

Topics

Evaluating and comparing the signalling and functional landscape of hiPSC-CMs derived from patients with dilated cardiomyopathy

Discussion

Member takes

Implication

Key Points

Structured PICO

Limitations

Cite This Study

Also Consider

Topics

Also Consider