Thomas J. LaRocca

All Publications

• Pharmacological Silencing of MicroRNA-152 Prevents Pressure Overload-Induced Heart Failure. Circulation. Heart failure LaRocca, T. J., Seeger, T. n., Prado, M. n., Perea-Gil, I. n., Neofytou, E. n., Mecham, B. H., Ameen, M. n., Chang, A. C., Pandey, G. n., Wu, J. C., Karakikes, I. n. 2020; 13 (3): e006298

  Abstract

  MicroRNAs are small, noncoding RNAs that play a key role in gene expression. Accumulating evidence suggests that aberrant microRNA expression contributes to the heart failure (HF) phenotype; however, the underlying molecular mechanisms are not well understood. A better understanding of the mechanisms of action of microRNAs could potentially lead to targeted therapies that could halt the progression or even reverse HF.We found that microRNA-152 (miR-152) expression was upregulated in the failing human heart and experimental animal models of HF. Transgenic mice with cardiomyocyte-specific miR-152 overexpression developed systolic dysfunction (mean difference, -38.74% [95% CI, -45.73% to -31.74%]; P<0.001) and dilated cardiomyopathy. At the cellular level, miR-152 overexpression perturbed mitochondrial ultrastructure and dysregulated key genes involved in cardiomyocyte metabolism and inflammation. Mechanistically, we identified Glrx5 (glutaredoxin 5), a critical regulator of mitochondrial iron homeostasis and iron-sulfur cluster synthesis, as a direct miR-152 target. Finally, a proof-of-concept of the therapeutic efficacy of targeting miR-152 in vivo was obtained by utilizing a locked nucleic acid-based inhibitor of miR-152 (LNA 152) in a murine model of HF subjected to transverse aortic constriction. We demonstrated that animals treated with LNA-152 (n=10) showed preservation of systolic function when compared with locked nucleic acid-control treated animals (n=9; mean difference, 18.25% [95% CI, 25.10% to 11.39%]; P<0.001).The upregulation of miR-152 expression in the failing myocardium contributes to HF pathophysiology. Preclinical evidence suggests that miR-152 inhibition preserves cardiac function in a model of pressure overload-induced HF. These findings offer new insights into the pathophysiology of HF and point to miR-152-Glrx5 axis as a potential novel therapeutic target.

  View details for DOI 10.1161/CIRCHEARTFAILURE.119.006298

  View details for PubMedID 32160771

• Comparison of Electrophysiologic Profiles in Pediatric Patients with Incidentally Identified Pre-Excitation Compared with Wolff-Parkinson-White Syndrome. The American journal of cardiology LaRocca, T. J., Beyersdorf, G. B., Li, W., Foltz, R., Patel, A. R., Tanel, R. E. 2019

  Abstract

  The rising utilization of screening electrocardiograms has resulted in increased incidental identification of ventricular pre-excitation in pediatric patients. We compared accessory pathways of incidentally identified pre-excitation to Wolff-Parkinson-White Syndrome (WPW) with the aim to identify factors important in preprocedural counseling and planning. This single-center, retrospective study of patients ≤18 years without congenital heart disease identified 227 patients diagnosed with pre-excitation and referred for invasive electrophysiology study between 2008 and 2017. WPW Syndrome was diagnosed in 178 patients, while 49 patients had incidental identification of pre-excitation. Anterograde conduction of incidentally identified accessory pathways was not clinically different between the two cohorts at baseline or upon isoproterenol infusion. However, the proportion of accessory pathways meeting high-risk criteria was significantly lower than in patients diagnosed with WPW, 12% versus 28% (p<0.05). Retrograde conduction at baseline of incidentally diagnosed accessory pathways was slower with a median block cycle length 365 milliseconds (IQR 260 to 450) versus 290 milliseconds (IQR 260 to 330, p<0.01). In the incidentally identified cohort, right-sided, paraHisian, and fascicular pathways were more common with fewer attempted ablations (71% vs 94%, p<0.001) and lower success rate (91% vs 97%, p<0.001). A binomial logistic regression analysis further indicated patients incidentally identified with pre-excitation were associated with having lower rates of inducible supraventricular tachycardia, atrial fibrillation, and ablations performed, in addition, to having right-sided pathways. In conclusion, as patients with incidentally identified pre-excitation present more frequently for consideration of invasive electrophysiology study, these results impact procedural approaches, technical considerations, patient counseling, and outcome expectations.

  View details for DOI 10.1016/j.amjcard.2019.04.053

  View details for PubMedID 31204032