Left ventricular non-compaction (LVNC) is a cardiomyopathy that may be of genetic origin; however, few data are available about the yield of mutation, the spectrum of genes and allelic variations. The aim of this study was to better characterize the genetic spectrum of isolated LVNC in a prospective cohort of 95 unrelated adult patients through the molecular investigation of 107 genes involved in cardiomyopathies and arrhythmias. Fifty-two pathogenic or probably pathogenic variants were identified in 40 patients (42%) including 31 patients (32.5%) with single variant and 9 patients with complex genotypes (9.5%).Mutated patients tended to have younger age at diagnosis than patients with no identified mutation. The most prevalent genes were TTN, then HCN4, MYH7, and RYR2. The distribution includes 13 genes previously reported in LVNC and 10 additional candidate genes.Our results show that LVNC is basically a genetic disease and support genetic counseling and cardiac screening in relatives. There is a large genetic heterogeneity, with predominant TTN null mutations and frequent complex genotypes. The gene spectrum is close to the one observed in dilated cardiomyopathy but with specific genes such as HCN4. We also identified new candidate genes that could be involved in this sub-phenotype of cardiomyopathy. K E Y W O R D Scardiomyopathy, left ventricular non-compaction, molecular genetic, next generation sequencing Gilbert Habib and Philippe Charron are equal last authors.

There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure. We have recently shown that cardiac fibrosis post-myocardial infarction (MI) can be regulated by resident cardiac cells with a fibrogenic signature and identified by the expression of PW1 (Peg3). Here we identify αV-integrin (CD51) as an essential regulator of cardiac PW1 + cells fibrogenic behavior. We used transcriptomic and proteomic approaches to identify specific cell-surface markers for cardiac PW1 + cells and found that αV-integrin (CD51) was expressed in almost all cardiac PW1 + cells (93% ± 1%), predominantly as the αVβ1 complex. αV-integrin is a subunit member of the integrin family of cell adhesion receptors and was found to activate complex of latent transforming growth factor beta (TGFβ at the surface of cardiac PW1 + cells. Pharmacological inhibition of αV-integrin reduced the profibrotic action of cardiac PW1 + CD51 + cells and was associated with improved cardiac function and animal survival following MI coupled with a reduced infarct size and fibrotic lesion. These data identify a targetable pathway that regulates cardiac fibrosis in response to an ischemic injury and demonstrate that pharmacological inhibition of αV-integrin could reduce pathological outcomes following cardiac ischemia. Heart failure (HF) remains a leading cause of mortality and hospitalization worldwide and represents a heavy financial burden on health care systems 1-6. Current pharmacological treatments limit the peripheral consequences of cardiac dysfunction, but therapeutic approaches that impact primary adverse cardiac remodeling at the myocardial level are limited. While the etiology of HF is diverse, HF is typically associated with a range of physiological and morphological changes including fibrosis within the myocardium 7-9. Cardiac fibrosis is characterized with the excessive production and deposition of extracellular matrix (ECM) proteins within the myocardium that results in normal tissue architecture disruption, reduced tissue compliance, and mechanical and electrical dysfunction, consequently leading to HF 10,11. The mechanisms underlying cardiac fibrosis are incompletely understood, thereby impeding the development of effective anti-fibrotic therapeutics to complement the current therapies for HF 9,11,12. Activated cardiac fibroblasts are essential for the production of ECM proteins that accumulate during cardiac fibrosis; however, recent studies have established that cardiac fibroblasts represent a heterogeneous cell population 10-14. The exact nature of activated fibroblasts and consequently the sources of cardiac fibrosis remain unclear 9,12. Different mechanisms underlying fibrosis have been reported including the activation and