Network medicine reveals myocardial regulatory vulnerability in schizophrenia

People with schizophrenia experience excess cardiovascular mortality, yet the myocardial substrate underlying this burden remains poorly understood. We hypothesised that schizophrenia is associated with a distinct myocardial regulatory state which increases myocardial vulnerability to toxic effects under antipsychotic stress. We applied a donor-resolved, multiscale framework to 190,590 left ventricular nuclei from 25 donors. Cell-state reconstruction, local differential-abundance analysis and covariate-aware latent-factor modelling resolved a recurrent cardiomyocyte state within the death-matched contrast. Donor-level expression and regulatory networks quantified its molecular output and regulatory coherence. Cardiovascular genetics, cross-tissue transcriptomics, disease and drug networks, pharmacovigilance and perturbational evidence positioned the programme across schizophrenia biology, cardiac risk and antipsychotic action. In silico cardiomyocyte perturbations tested the consequences of selectively disrupting physiological coordination under drug stress. After adjusting for the myocardial background shared across sudden-death cases, schizophrenia was found to associate with a recurrent cardiomyocyte state characterized by preserved molecular output yet broadly diminished regulatory coherence. A stable 71-gene cardiomyocyte programme spanning contraction, energetics and calcium handling captured this state. The output–coherence decoupling was supported by exact donor-level inference ( P = 0.0156) and leave-one-donor-out stability analysis. The programme intersected a schizophrenia-associated anterior cingulate network, showed the strongest cardiovascular genetic enrichment for ventricular repolarisation, and occupied arrhythmia and cardiomyopathy disease networks. Antipsychotic drug targets mapped to the same cardiac network space, while excess arrhythmia reporting replicated across non-overlapping pharmacovigilance periods (overall reporting odds ratio, 4.24). Progressive marginal-preserving disruption of physiological coordination among selected calcium-control axes broadened calcium-response distributions and abnormal electrophysiological tails under drug stress, with stronger effects within the calcium-control axis family. Across 13,205 perturbagens, expression response was essentially unrelated to regulatory-topology response (Spearman ρ = 0.007; AUROC = 0.495). Schizophrenia was associated with a distinct myocardial vulnerability state beyond the shared cardiac background, connecting schizophrenia biology, ventricular repolarisation, cardiovascular disease networks and antipsychotic drug-target space. The state was defined by weakened regulatory organisation despite preserved molecular output, while physiological robustness under drug stress emerged from coordinated system organisation rather than from individual components in isolation. Cardiac drug safety may therefore depend not only on the perturbation itself, but also on the regulatory state of the myocardium that receives it.