Martinez-Fernandez, Almudena

Background Cardiac resynchronization therapy using bi‐ventricular pacing is proven effective in the management of heart failure (HF) with a wide QRS ‐complex. In the absence of QRS prolongation, however, device‐based resynchronization is reported unsuitable. As an alternative, the present study tests a regenerative cell‐based approach in the setting of narrow QRS ‐complex HF. Methods and Results Progressive cardiac dyssynchrony was provoked in a chronic transgenic model of stress‐triggered dilated cardiomyopathy. In contrast to rampant end‐stage disease afflicting untreated cohorts, stem cell intervention early in disease, characterized by mechanical dyssynchrony and a narrow QRS ‐complex, aborted progressive dyssynchronous HF and prevented QRS widening. Stem cell‐treated hearts acquired coordinated ventricular contraction and relaxation supporting systolic and diastolic performance. Rescue of contractile dynamics was underpinned by a halted left ventricular dilatation, limited hypertrophy, and reduced fibrosis. Reverse remodeling reflected a restored cardiomyopathic proteome, enforced at systems level through correction of the pathological molecular landscape and nullified adverse cardiac outcomes. Cell therapy of a dyssynchrony‐prone cardiomyopathic cohort translated prospectively into improved exercise capacity and prolonged survivorship. Conclusions In narrow QRS HF, a regenerative approach demonstrated functional and structural benefit, introducing the prospect of device‐autonomous resynchronization therapy for refractory disease.

Mammalian heart development is built on highly conserved molecular mechanisms with polygenetic perturbations resulting in a spectrum of congenital heart diseases (CHD). However, knowledge of cardiogenic ontogeny that regulates proper cardiogenesis remains largely based on candidate-gene approaches. Mapping the dynamic transcriptional landscape of cardiogenesis from a genomic perspective is essential to integrate the knowledge of heart development into translational applications that accelerate disease discovery efforts toward mechanistic-based treatment strategies. Herein, we designed a time-course transcriptome analysis to investigate the genome-wide dynamic expression landscape of innate murine cardiogenesis ranging from embryonic stem cells to adult cardiac structures. This comprehensive analysis generated temporal and spatial expression profiles, revealed stage-specific gene functions, and mapped the dynamic transcriptome of cardiogenesis to curated pathways. Reconciling known genetic underpinnings of CHD, we deconstructed a disease-centric dynamic interactome encoded within this cardiogenic atlas to identify stage-specific developmental disturbances clustered on regulation of epithelial-to-mesenchymal transition (EMT), BMP signaling, NF-AT signaling, TGFb-dependent EMT, and Notch signaling. Collectively, this cardiogenic transcriptional landscape defines the time-dependent expression of cardiac ontogeny and prioritizes regulatory networks at the interface between health and disease.